JP2014055156A - Compound and method for inhibiting interaction of bcl protein with binding partner - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an isoxazolidine compound.SOLUTION: One aspect of the present invention relates to heterocyclic compounds that bind to bcl proteins and inhibit Bcl function. Another aspect of the present invention relates to compositions comprising the heterocyclic compound of the invention. The present invention provides methods for treating and modulating disorders associated with hyperproliferation, such as cancer.

Description

RELATED APPLICATION This application claims priority based on US patent application Ser. No. 11 / 600,332 filed Nov. 15, 2006, which is hereby incorporated by reference in its entirety.

The present invention relates to the field of cancer treatment. Specifically, the present invention is in the field of cancer therapy that promotes apoptosis in tumor cells using isoxazolidine analogs. The isoxazolidine compounds of the present invention bind to Bcl protein and block Bcl anti-apoptotic function in cancer cells and tumor tissues that express Bcl protein. The compounds and pharmaceutical compositions containing these compounds can be used alone or in combination with chemotherapeutic agents or other drugs in the treatment of cancer diseases.

BACKGROUND OF THE INVENTION Apoptosis, or programmed cell death, is important for normal embryonic development / anatomical development, host defense, and suppression of tumor formation. Incomplete regulation of apoptosis has been implicated in cancer and many other human diseases resulting from imbalances between the processes of cell division and cell death. Bcl-2 was originally identified at the chromosomal breakpoint of B cell lymphoma with t (14; 18) and belongs to the growth family of proteins that regulate apoptosis (Gross, A; McDonnell, JM; Korsmeyer, SJ BCL- 2 family members and the mitochondria in apoptosis.Genes & Development 1999, 13, 1899-1911, Cory, S .; Huang, DCS; Adams, JM The Bcl-2 family: roles in cell survival and oncogenesis.Oncogene, 2003 22, Danial, NN; Korsmeyer, SJ Cell death: Critical control points. Cell 2004, 116, 205-218. Chao, DT; Korsmeyer, SJ Bcl-2 family: regulators of cell death. Annu. Rev. Immunol. 1998, 16, 395-419) .. Apoptosis, Christopher Potten, James Wilson, Cambridge University Press, 2004). The Bcl-2 family of proteins includes both anti-apoptotic molecules such as Bcl-2 and Bcl-XL and pro-apoptotic molecules such as Bax, Bak, Bid and Bad. Bcl-2 contributes to cancer cell progression by blocking normal cell turnover caused by physiological cell death mechanisms. Overexpression of Bcl-2 has been observed in 70% of breast cancer and many other forms of cancer (Buolaniwini, JK Novel anticancer drug discovery. Curr. Opin. Chem. Biol. 1999, 3, 500-509) . Bcl-2 protein expression levels are also correlated with resistance to a wide range of chemotherapeutic agents and gamma-radiotherapy (Reed, JC; Miyashita, T .; Takayama, S .; Wang, H.-G .; Sato, T .; Krajewski, S .; Aime-Sempe, C .; Bodrug, S .; Kitada, S .; Hanada, M. Bcl-2 family proteins: Regulators of cell-death involved in the pathogenesis of cancer and resistance to therapy J. Cell. Biochem. 1996, 60, 23-32; Reed, JC Bcl-2 family proteins: strategies for overcoming chemoresistance in cancer.Advances in Pharmocology 1997, 41, 501-553; Strasser, A .; Huang, DCS ; Vaux, DL The role of the Bcl-2 / ced-9 gene family in cancer and general implications of defects in cell death control for tumorigenesis and resistance to chemotherapy. Biochem. Biophys. Acta 1997, 1333, F151-F189; DiPaola, RS; Aisner, J. Overcoming Bcl-2- and p53-mediated resistance in prostate cancer. Semin. Oncol. 1999, 26, 112-116).

Members of the Bcl-2 family of proteins are important for apoptosis with pro-apoptotic functions (eg Bax, Bak, Bid, Bim, Noxa, Puma) and anti-apoptotic functions (eg Bcl-2, Bcl-xL, Mcl-1) The adjustment factor is shown. Selective and competitive dimerization between pro- and anti-apoptotic members of the family determines the fate of cells given pro-apoptotic stimuli. The exact role of Bcl-2 and Bcl-xL in cancer is not fully understood, but Bcl-2 and Bcl-xL only contribute to cancer progression by preventing normal cell turnover There is no evidence to suggest that it is involved in the resistance of cancer cells to current cancer therapies. Experimental overexpression of Bcl-2 (Bcl-xL) provides a broad spectrum of chemotherapeutic agents and radiation-resistant cancer cells (Bcl-2 family proteins: Regulators of cell-death involved in the pathogenesis of cancer J. Cell. Biochem. 1996, 60, 23-32; Reed, J. C). Bcl-2 and / or Bcl-xL is overexpressed in over 50% of all tumors listed below (from Wang, S .; Yang, D .; Lippman, ME Targeting Bcl-2 and Bcl-xL with nonpeptidic small-molecule antagonists. Seminars in Oncology, 2003, 5, 133-142).

  Biological approaches to modulate Bcl-2 function using antisense oligonucleotides or single chain antibodies have been shown to enhance tumor cell sensitivity (Ziegler, A .; Luedke, GH; Fabbro, D .; Altmann, KH; Stahel, RA; Zangemeister-Wittke, U. Induction of apoptosis in small-cell lung cancer cells by an antisense oligodeoxynucleotide targeting the Bcl-2 coding sequence. J. Natl. Cancer. Inst. 1997, 89 , 1027-1036; Webb, A .; Cunningham, D .; Cotter, F .; Clarke, PA; Di Stefano, F .; Ross, P .; Corpo, M .; Dziewanowska, Z. Bcl-2 antisense therapy in Patients with non-hodgkin lymphoma. Lancet 1997, 349, 1137-1141; Cotter, FE Phase I clinical and pharmacokinetic study of Bcl-2 antisense oligodeoxynucleotide therapy in patients with non-hodgkin's lymphoma. J. Clin. Oncol. 2000, 18, 1812-1823; Piche, A .; Grim, J .; Rancourt, C .; Gomez-Navarro, J .; Reed, JC; Curiel, DT Modulation of Bcl-2 protein levels by an intracellular anti-Bcl-2 single-chain antibody increases drug-induced cytotoxicity in the breast cancer cell line MCF-7. Cancer Res. 1998, 58, 2134-2140).

  Antisense oligonucleotide (G3139) designed to hybridize to sequences in Bcl-2 mRNA (Raynaud, FI; Orr, RM; Goddard, PM; Lacey, HA; Lancashire, H .; Judson, IR; Beck, T .; Bryan, B .; Cotter, FE Pharmacokinetics of G3139, a phosphorothioate oligodeoxynucleotide antisense to Bcl-2, after intravenous administration or continuous subcutaneous infusion to mice. J. Pharmacol. Exp. Ther. 1997, 281, 420-427) It has been shown to inhibit Bcl-2 expression, induce apoptosis, and inhibit cell proliferation in human breast cancer cells with Bcl-2 overexpression (Chen, HX, Marchall, JL, Trocky, N., Baidas , S., Rizvi, N., Ling, Y., Bhagava, P., Lippman, ME, Yang, D., and Hayes, DF A Phase I study of Bcl-2 antisense G3139 (Genta) and weekly docetaxel in patients with advanced breast cancer and other solid tumors. Proceedings of American Society of Clinical Oncology, 2000). Importantly, synergy and complete tumor regression was observed with G3139 plus docetaxel combination therapy in vivo. Bcl-2 therefore represents a very attractive target for the development of new therapies for the treatment of many forms of cancer.

  Limitations regarding the use of large molecules such as oligonucleotides, proteins and polypeptides as therapeutic agents include low oral availability, in vivo stability and high cost. A more desirable therapeutic agent would be a non-peptide cell permeable small molecule that binds to Bcl-2, blocks anti-apoptotic functions in cancer, and promotes cell death in tumors.

  Various small molecules have been shown to inhibit the function of Bcl-2. For example, acyl sulfonamides have been shown to inhibit the function of Bcl-2 and Bcl-xL in biochemical and in vitro assays (Nature (2005) 435, 677-681). However, there is a need for another small organic molecule that binds to Bcl-2, blocks its anti-apoptotic function in cancer, and promotes cell death in tumors. The present invention achieves this need and has other related advantages.

SUMMARY OF THE INVENTION One aspect of the present invention relates to isoxazolidine compounds. In some cases, the nitrogen atom of the isoxazolidine ring is attached to a substituted aralkyl group. In certain instances, the substituted aralkyl group is a substituted benzyl group. In some cases, the isoxazolidine ring is substituted with a hydroxymethyl or hydroxyethyl group. In some cases, the isoxazolidine ring is substituted with hydroxymethyl and hydroxyethyl groups. In some cases, the isoxazolidine ring is substituted with an amide group. The present invention further provides pharmaceutically active salts of the above isoxazolidine compounds. Another aspect of the present invention relates to a pharmaceutical composition comprising the isoxazolidine compound of the present invention. Another aspect of the present invention relates to a method of using the above compound or a pharmaceutically active salt thereof alone or in combination with other drugs for treating cancer. Specifically, the present invention provides a pathological condition characterized by pathological growth of mammalian cells such as tumor cells (eg, breast cancer and myeloid leukemia) with an effective amount of a compound of the present invention in a mammal suffering from such a pathological condition. A method of treatment is provided that comprises treating by administering to an animal or human. In some cases, the compounds of the invention are administered with a pharmaceutically acceptable carrier.

Detailed Description of the Invention The present invention relates generally to isoxazolidine compounds useful in the treatment of cancer. The isoxazolidine compounds of the present invention bind to one or more Bcl proteins and block Bcl anti-apoptotic function in cancer cells and tumor tissues that express the Bcl protein. In some embodiments, some compounds of the present invention selectively inhibit the anti-apoptotic activity of a single member of the Bcl-2 subfamily of anti-apoptotic proteins. The isoxazolidine compound of the present invention can be used to treat patients suffering from diseases related to Bcl. In some cases, the isoxazolidine compounds of the invention are used to treat patients suffering from cancer. The isoxazolidine compound of the present invention can be administered to a patient in the form of a pharmaceutical composition. The pharmaceutical composition comprises an isoxazolidine compound of the invention and one or more pharmaceutically acceptable excipients. In some cases, the pharmaceutical composition comprises an isoxazolidine compound of the invention, a chemotherapeutic agent and one or more pharmaceutically acceptable excipients. In some cases, the chemotherapeutic agent is docetaxel, paclitaxel, cisplatin, 5-FU, doxorubicin, epipodophyllotoxin, camptothecin, 17-AAG or cyclophosphamide.

Synthesis of Isoxazolidine Compound The isoxazolidine compound of the present invention can be produced using a [3 + 2] cycloaddition reaction between nitrone and alkene. Nitrone substrates and alkenes can contain functional groups suitable for synthesis of isoxazolidine cores followed by chemical derivatization. In some cases, Lewis acid is added to the reaction. In a preferred embodiment, the Lewis acid is Ti (Oi-Pr) ₄ . In some cases, the reaction mixture is subjected to microwave irradiation. In general, the target reaction is carried out in a liquid reaction medium, but can also be carried out on a solid support. The reaction can be carried out in an aprotic solvent, preferably the reaction components are substantially soluble. Suitable solvents include ethers such as diethyl ether, 1,2-dimethoxyethane, diglyme, t-butylmethyl ether, tetrahydrofuran; halogenated solvents such as chloroform, dichloromethane, dichloroethane, chlorobenzene, carbon tetrachloride; benzene, xylene, Aliphatic and aromatic hydrocarbon solvents such as toluene, hexane, pentane; esters and ketones such as ethyl acetate, acetone and 2-butanone; polar aprotic solvents such as acetonitrile, dimethyl sulfoxide, dimethylformamide, pyridine; or 2 or more A combination of these solvents may be mentioned. The reaction can be carried out at various temperatures. In general, reactions carried out at low temperatures take longer to reach completion. In some cases, the cycloaddition reaction is performed in the range of about 15 ° C to about 60 ° C. In some cases, the cycloaddition reaction is performed in the range of about 15 ° C to about 30 ° C. In some cases, the cycloaddition reaction is performed at about room temperature. In some cases, the cycloaddition reaction is performed in the range of about 80 ° C to about 150 ° C. In some cases, the cycloaddition reaction is performed in the range of about 90 ° C to about 120 ° C. In some cases, the cycloaddition reaction is performed in the range of about 95 ° C to about 105 ° C. In some cases, the cycloaddition reaction is performed using a substrate supported on a solid support. Following synthesis of the isoxazolidine core, the isoxazolidine compound can be derivatized using various functionalization reactions known in the art. Typical examples include palladium coupling reactions to alkenyl halides or aryl halides, oxidation, reduction, reaction with nucleophiles, reaction with electrophiles, pericyclic reactions, introduction of protecting groups, removal of protecting groups. Etc.

Biological Activity Analysis The following in vitro binding and cellular assays can be used to determine the activity and specificity of compounds of the invention that bind to Bcl-2 and inhibit intracellular Bcl-2 function.

Bcl-2 binding assay
Bcl-2 and Bcl-xL binding can be measured using various known methods. One such assay is described in the literature (Wang, J.-L .; Zhang, Z-J .; Choksi, S .; Sjam. S .; Lu, Z .; Croce, CM; Alnemri, ES; Komgold, R .; Huang, Z. Cell-permeable Bcl-2 binding peptide: A chemical approach to induce apoptosis in tumor cells. Sensitivity using fluorescence polarization (FP) as described in Cancer Res. 2000, 60, 1498-1502) Quantitative in vitro binding assay.

Cell-based assay The ability of the isoxazolidine compounds of the present invention to inhibit cell viability with Bcl-2 protein overexpression in cancer cells was demonstrated. When RL-cells are exposed to an isoxazolidine compound of the invention, the inhibitor exhibits a dose-dependent cell killing with an IC ₅₀ value of about 100 μM to about 1 μM in an Alamar Blue cytotoxicity assay (see Examples) ). When Panc1 cells are exposed to an isoxazolidine compound of the present invention in combination with camptothecin, the inhibitor produces a synergistic dose-dependent cell killing of an IC ₅₀ value of about 100 μM to about 1 μM in a propidium iodide exclusion cell viability assay. Shown (see Examples).

  Bcl-2 inhibitors can be used as single agents in breast cancer (US 2003/0119894, published PCT applications WO 02/097053 and WO 02/13833), lymphomas (Nature (2005) 435, 677-681), small cell lung cancer ( Nature (2005) 435, 677-681), head and neck cancer (published PCT application WO 02/097053) and leukemia (published PCT application WO 02/13833), but many Have been shown to be active against cancer cell lines.

  Bcl-2 inhibitors can be used in combination with other anticancer drugs and radiation in breast cancer (in combination with docetaxel, published PCT application WO 02/097053), prostate cancer (in combination with docetaxel, published PCT application WO 02/097053), including head and neck cancer (in combination with docetaxel, published PCT application WO 02/097053) and non-small cell lung cancer (in combination with paclitaxel, Nature (2005) 435, 677-681) Have been shown to be active against many cancer cell lines, including but not limited to these. In addition to the above combination chemotherapeutic agents, small molecule inhibitors of Bcl-2 protein include, but are not limited to, etoposide, doxorubicin, cisplatin, paclitaxel and radiation (Nature (2005) 435, 677-681) Synergy with other anticancer agents.

Therapies and Methods of Treatment The present invention further provides methods of treating and reducing the severity of cancer and other Bcl-mediated disorders or conditions.
Cancer or neoplastic diseases and related disorders that can be treated by administration of the compounds and compositions of the present invention include, but are not limited to, those listed in Table 1 (for a review of such disorders, see Fishman et al. al., 1985, Medicine, 2d Ed., JB Lippincott Co., Philadelphia):

Table 1
Cancer and neoplastic disease
Leukemia acute leukemia acute lymphoblastic leukemia acute myeloid leukemia myeloblast promyelocytic myelomonocytic monocytic erythroleukemia chronic leukemia chronic myeloid (granulocytic) leukemia chronic lymphocytic leukemia erythrocytosis lymphoma Hodgkin Disease non-Hodgkin's disease multiple myeloma Waldenstrom macroglobulinemia heavy chain disease solid tumor sarcoma and carcinoma fibrosarcoma myxosarcoma liposarcoma chondrosarcoma osteosarcoma chordoma hemangiosarcoma lymphangiosarcoma lymphatic endothelial sarcoma synovial tumor mesothelioma Ewing tumor Leiomyosarcoma Rhabdomyosarcoma Colon cancer Pancreatic cancer Breast cancer Ovarian cancer Prostate cancer Squamous cell carcinoma Adenocarcinoma Sweat gland cancer Sebaceous gland Cancer papillary cancer Papillary gland cancer Cystic gland Cancer Medullary cancer Bronchial cancer Renal cell cancer Liver cancer Bile duct cancer Choriocarcinoma Seminoma Embryonic cancer Wilms tumor Cervical cancer Uterine cancer Testicular tumor Lung N-small cell lung cancer bladder cancer epithelial cancer glioma astrocytoma medulloblastoma craniopharyngioma ependymoma pineal gland tumor hemangioblastoma acoustic neuroma oligodendroglioma meningioma melanoma neuroblastoma
Retinoblastoma

  In a preferred embodiment, the compound of the invention comprises a lymphoma (preferably follicular lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma or chronic lymphocytic leukemia), prostate cancer (more preferably non-hormonal). Sensitivity), breast cancer (preferably estrogen receptor positive), neuroblastoma, colorectal, endometrium, ovary, lung (preferably small cells), hepatocellular carcinoma, multiple myeloma, head and neck Or used to treat cancer, including but not limited to testicular cancer (preferably germ cells).

Treatment of cancer in combination with chemotherapy or radiotherapy In some embodiments, one or more of the compounds of the present invention is methotrexate, taxol, mercaptopurine, thioguanine, hydroxyurea, cytarabine, cyclophosphamide, ifosfamide. , Nitrosourea, cisplatin, carboplatin, mitomycin, dacarbazine, procarbazine, etoposide, prednisolone, dexamethasone, cytarbine, camptothecin, bleomycin, doxorubicin, idarubicin, daunorubicin, dactinomycin, dactinomycin, dactinomycin Including, but not limited to, throne, asparaginase, vinblastine, vincristine, vinorelbine, paclitaxel and docetaxel, Used to treat or prevent cancer or neoplastic disease in combination with one or more anticancer drugs or chemotherapeutic agents. In preferred embodiments, the one or more compounds of the present invention include, but are not limited to, those in combination with one or more chemotherapeutic agents or other anticancer agents, including but not limited to those shown in Table 2. Used to treat or prevent cancer or neoplastic diseases.

Table 2
Chemotherapeutics and other anticancer agents
Radiation: γ-radiation
Alkylating agent <br/> Nitrogen Mustard: Cyclophosphamide
Ifosfamide
Trophosphamide
Chlorambucil
Estramustine
Melphalan nitrosourea: Carmustine (BCNU)
Lomustine (CCNU)
Alkyl sulfonate busulfan
Threosulfane triazene: Dacarbazine platinum-containing compound: cisplatin
Carboplatin
Oxaplatin
Plant alkaloids <br/> Vinca alkaloids: Vincristine
Vinblastine
Vindesine
Vinorelbine Taxoid: Paclitaxel
Docetaxol
DNA topoisomerase inhibitor Epipodophylline: Etoposide
Teniposide
Topotecan
9-aminocamptothecin
Camptoirinotecan
Chrisnatore
Mitomycin <br/> Mitomycin C Mitomycin C
Antimetabolite
Antifolate:
DHFR inhibitor: methotrexate
Trimetrexate
IMP dehydrogenase inhibitor: Mycophenolic acid
Triazofurin
Ribavirin
EICAR
Ribonucleotide reductase inhibitor: Hydroxyurea
Deferoxamine
Pyrimidine analogs:
Uracil analog 5-fluorouracil
Floxuridine
Doxyfluridine
Ratitrexed
Capecitabine cytosine analog Cytarabine (ara C)
Cytosine arabinoside
Fludarabine purine analogue: mercaptopurine
Thioguanine hormone therapy:
Receptor antagonist:
Antiestrogen Tamoxifen
Raloxifene
Megestrol
LHRH agonist: goscrclin
Leuprolide acetate antiandrogen: flutamide
Bicalutamide
Retinoid / Dertoid Vitamin D3 analogue: EB 1089
CB 1093
KH 1060
Photodynamic therapy: Belt porphin
(Vertoporfin, BPD-MA)
Phthalocyanine
Photosensitizer Pc4
Demethoxy-Hypocrellin A
(2BA-2-DMHA)
Cytokines: Interferon alpha
Interferon gamma
Tumor necrosis factor
Other:
Isoprenylation inhibitors: Lovastatin dopaminergic neurotoxin: 1-methyl-4-phenylpyridiniumio
Cell cycle inhibitors: Staurosporine actinomycin: Actinomycin D
Dactinomycin bleomycin: bleomycin A2
Bleomycin B2
Peplomycin anthracycline: Daunorubicin
Doxorubicin (adriamycin)
Idarubicin
Epirubicin
Pilarubicin
Zorubicin
Mitoxantrone
MDR inhibitor: Verapamil
Ca ²⁺ ATPase inhibitor: thapsigargin antibody Avastin
Erbitux
Rituxan
Other prednisolone
Imatinib
thalidomide
Lenalidomide
Bortezomib
Gemcitabine
Erlotinib
Gefitinib
Sorafenib
Stinib

  Chemotherapeutic agents and / or radiation therapy can be administered by therapeutic protocols well known in the art. It will be apparent to those skilled in the art that administration of a chemotherapeutic agent and / or radiation therapy can vary depending on the disease being treated and the known effects of chemotherapeutic agents and / or radiation treatment on the disease. Also, according to the knowledge of a skilled clinician, the treatment protocol (eg, dosage and administration time) can be determined based on the observed effect on the patient of the administered therapeutic agent (ie, an anti-tumor agent or radiation), and the administered therapeutic agent. May vary in view of the observed response of the disease.

  In general, the compound of the present invention and the chemotherapeutic agent need not be administered in the same pharmaceutical composition, but can be administered by different routes due to different physical and chemical properties. For example, the compounds of the present invention can be administered intravenously to produce and maintain good blood levels, while chemotherapeutic agents can be administered orally. The determination of the mode of administration in the same pharmaceutical composition, and possibly the validity of the administration, is within the knowledge of a well-trained clinician. Initial administration can be performed by established protocols known in the art, and then the dosage, dosage form, and administration time can be modified by a skilled clinician based on the observed effects.

  The specific choice of chemotherapeutic agent or radiation will depend on the diagnosis of the attending physician and the judgment of the patient's condition and appropriate treatment protocol.

  The compound of the invention and the chemotherapeutic agent and / or radiation may be the nature of the proliferative disease, the pathology of the patient, and the chemotherapeutic agent to be administered in conjunction with the compound of the invention (ie, within a single treatment protocol) and / or Depending on the substantial choice of radiation, they can be combined (eg, simultaneously, substantially simultaneously or within the same treatment protocol) or administered sequentially.

  Where the compound of the present invention and the chemotherapeutic agent and / or radiation are not administered simultaneously or substantially simultaneously, the optimal order of administration of the compound of the present invention and the chemotherapeutic agent and / or radiation may be different for different tumors. Thus, in some cases, a compound of the invention can be administered first, followed by chemotherapeutic agents and / or radiation; in other cases, chemotherapeutic agents and / or radiation can be administered first, then The compound of the present invention can be administered. This alternative administration can be repeated during a single treatment protocol. The determination of the order of administration of each therapeutic agent and the number of repetitions of administration between treatment protocols is well within the knowledge of a skilled clinician after evaluation of the disease being treated and the condition of the patient. For example, a chemotherapeutic agent and / or radiation is administered first, particularly if it is a cytotoxic agent, followed by treatment with administration of a compound of the invention, and if determined to be advantageous, a chemotherapeutic agent And / or administration of radiation or the like can continue until the treatment protocol is complete.

  Thus, according to experience and knowledge, the clinician will specify each protocol for the administration of therapeutic components (therapeutic agents, ie compounds of the invention, chemotherapeutic agents or radiation) according to the needs of the individual patient as treatment progresses. Can be modified.

Definitions For convenience, certain terms used in the specification, examples, and claims are collected here.
The terms “combination” and “combination” refer to simultaneous administration (simultaneous administration of two or more therapeutic agents) and time-varying administration (time different from the administration time of another therapeutic agent) as long as the therapeutic agents are present in the patient to some extent at the same time. Means administration of one or more therapeutic agents).

  As used herein, the term “heteroatom” means any atom other than carbon or hydrogen. Preferred heteroatoms are boron, nitrogen, oxygen, phosphorus, sulfur and selenium.

The term “alkyl” refers to saturated aliphatic groups such as straight chain alkyl groups, branched chain alkyl groups, cycloalkyl (alicyclic) groups, alkyl substituted cycloalkyl groups, and cycloalkyl substituted alkyl groups. In preferred embodiments, a straight chain or branched chain alkyl has 30 or fewer, more preferably 20 or fewer carbon atoms in its backbone (eg, C ₁ -C ₃₀ for straight chain, C _3- for branched chain). C ₃₀ ). Likewise, preferred cycloalkyls have from 3-10 carbon atoms in their ring structure, and more preferably have 5, 6 or 7 carbons in the ring structure.

  Unless otherwise specified, the term “lower alkyl” as used herein is an alkyl group as defined above, but contains 1 to 10 carbons, more preferably 1 to 6 carbon atoms in its skeletal structure. It means what you have. Similarly, “lower alkenyl” and “lower alkynyl” have similar chain lengths. Preferred alkyl groups are lower alkyl. In preferred embodiments, the substituents designated herein as alkyl are lower alkyl.

As used herein, the term “haloalkyl” refers to an alkyl group in which any one to all hydrogens are replaced by a halide. “Perhaloalkyl” is one in which all hydrogens are replaced by halides.
As used herein, the term “aralkyl” refers to an alkyl group substituted with an aryl group (eg, an aromatic or heteroaromatic group).
The terms “alkenyl” and “alkynyl” refer to unsaturated aliphatic groups that are similar in chain length and can be substituted for the alkyl, but each contain at least one double or triple bond.

As used herein, the term “aryl” refers to 5-, 6-, and 7-membered monocyclic aromatic groups that can contain from 0 to 4 heteroatoms, such as benzene, anthracene, naphthalene, pyrene, pyrrole, furan. Thiophene, imidazole, oxazole, thiazole, triazole, pyrazole, pyridine, pyrazine, pyridazine and pyrimidine. Aryl groups having heteroatoms in the ring structure can also be referred to as “aryl heterocycles” or “heteroaromatics”. Aromatic rings can be substituted as described above, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amide, phosphonate, phosphinate, carbonyl, carboxyl, silyl , Ethers, alkylthios, sulfonyls, sulfonamides, ketones, aldehydes, esters, heterocyclyls, aromatic or heteroaromatic moieties, —CF ₃ , —CN, etc., can be substituted at one or more ring positions. The term “aryl” also refers to two or more cyclic rings in which two or more carbons are in common with two adjacent rings (a ring is a “fused ring”; where at least one ring is aromatic, eg Other cyclic rings also include polycyclic ring systems having cycloalkyl, cycloalkenyl, cycloalkynyl, aryl and / or heterocyclyl).

  The terms ortho, meta and para apply to 1,2-, 1,3- and 1,4-disubstituted benzenes, respectively. For example, 1,2-dimethylbenzene and ortho-dimethylbenzene are synonymous.

The term “heterocyclyl” or “heterocyclic group” means a 3- to 10-membered ring structure, more preferably a 3- to 7-membered ring, the ring structure containing 1 to 4 heteroatoms. Heterocycles can also be polycycles. Examples of the heterocyclyl group include thiophene, thianthrene, furan, pyran, isobenzofuran, chromene, xanthene, phenoxathiin, pyrrole, imidazole, pyrazole, isothiazole, isoxazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole , Indole, indazole, purine, quinolidine, isoquinoline, quinoline, phthalazine, naphthyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, pyrimidine, phenanthroline, phenazine, phenalsazine, phenothiazine, furazane, phenoxazine, Pyrrolidine, oxolane, thiolane, oxazole, piperidine, piperazine, morpholine, lacquer Down, lactams such as azetidinones and pyrrolidinones, sultams, sultones, and the like. Heterocyclic rings are as described above, for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amide, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, alkylthio, Substitution can be made at one or more positions with substituents such as sulfonyl, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, —CF ₃ , —CN.

The term “polycyclyl” or “polycyclic group” means two or more rings (eg, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl and / or heterocyclyl), wherein two or more carbons are two adjacent. In common with a ring, for example, a ring is a “fused ring”. Rings that are joined through non-adjacent atoms mean a “bridged” ring. Each of the polycyclic rings is as described above, for example, halogen, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, amino, nitro, sulfhydryl, imino, amide, phosphonate, phosphinate, carbonyl, carboxyl, silyl, ether, It can be substituted with substituents such as alkylthio, sulfonyl, ketone, aldehyde, ester, heterocyclyl, aromatic or heteroaromatic moiety, —CF ₃ , —CN and the like.

As used herein, the term “nitro” means —NO ₂ ; the term “halogen” is —F, —Cl, —Br or —I; the term “sulfhydryl” means —SH; the term “hydroxyl” Means —OH; the term “sulfonyl” means —SO ₂ —.

［式中、R50、R51およびR52はそれぞれ独立して、水素、アルキル、アルケニル、-(CH₂)_m-R61であるか、またはR50およびR51はそれらが結合しているN原子と一緒になって、環構造にて4〜8の原子を有するヘテロ環を形成し；R61はアリール、シクロアルキル、シクロアルケニル、ヘテロ環または多環であり；mはゼロまたは1〜8の範囲の整数である］
で示すことができる部分を意味する。いくつかの具体的態様にて、R50またはR51の一方のみがカルボニルであることができ、例えばR50、R51および窒素は一緒になってイミドを形成しない。他の具体的態様にて、R50およびR51（場合によりR52）はそれぞれ独立して水素、アルキル、アルケニルまたは-(CH₂)_m-R61である。従って、用語「アルキルアミン」は結合した置換または非置換アルキルを有する上記に定義されるアミン基を含み、すなわちR50およびR51の少なくとも一方はアルキル基である。 The terms “amine” and “amino” are known in the art and include both unsubstituted and substituted amines, such as the general formula:

[Wherein R50, R51 and R52 are each independently hydrogen, alkyl, alkenyl, — (CH ₂ ) _m —R61, or R50 and R51 together with the N atom to which they are attached. Forming a heterocycle having 4 to 8 atoms in the ring structure; R61 is aryl, cycloalkyl, cycloalkenyl, heterocycle or polycycle; m is zero or an integer in the range of 1-8 ]
Means the part that can be indicated by In some embodiments, only one of R50 or R51 can be carbonyl, for example R50, R51 and nitrogen together do not form an imide. In other embodiments, R50 and R51 (optionally R52) are each independently hydrogen, alkyl, alkenyl, or — (CH ₂ ) _m —R61. Thus, the term “alkylamine” includes an amine group as defined above having a substituted or unsubstituted alkyl attached, ie, at least one of R50 and R51 is an alkyl group.

［式中、R50は上記に定義されるとおりであり、R54は水素、アルキル、アルケニルまたは-(CH₂)_m-R61であり、mおよびR61は上記に定義されるとおりである］
で示すことができる部分を意味する。 The term “acylamino” is known in the art and has the general formula:

[Wherein R50 is as defined above, R54 is hydrogen, alkyl, alkenyl or — (CH ₂ ) _m —R61, and m and R61 are as defined above]
Means the part that can be indicated by

［式中、R50およびR51は上記に定義されるとおりである］
で示すことができる部分が挙げられる。本発明におけるアミドのいくつかの具体的態様は不安定であることがあるイミドを含まない。 The term “amide” is known in the art as an amino-substituted carbonyl and has the general formula:

[Wherein R50 and R51 are as defined above]
The part which can be shown by is mentioned. Some embodiments of the amide in the present invention do not include imides that may be unstable.

The term “alkylthio” means an alkyl group as defined above having a sulfur group attached. In some embodiments, the “alkylthio” moiety is —S-alkyl, —S-alkenyl, —S-alkynyl, and —S— (CH ₂ ) _m —R61, wherein m and R61 are as defined above. One). Typical alkylthio groups include methylthio, ethylthio, and the like.

［式中、X50は結合であるか、または酸素もしくは硫黄であり、R55およびR56は水素、アルキル、アルケニル、-(CH₂)_m-R61または医薬的に許容される塩であり、R56は水素、アルキル、アルケニルまたは-(CH₂)_m-R61であり、mおよびR61は上記に定義されるとおりである］
で示すことができる部分が挙げられる。X50が酸素であり、R55またはR56が水素でない場合、式は「エステル」である。X50が酸素であり、R55が上記に定義されるとおりである場合、該部分は本明細書にてカルボキシル基とも称され、特にR55が水素である場合、式は「カルボン酸」である。X50が酸素であり、R56が水素である場合、式は「ホルメート」である。一般に、上記式の酸素原子が硫黄で置き換えられる場合、式は「チオールカルボニル」基である。X50が硫黄であり、R55またはR56が水素でない場合、式は「チオールエステル」である。X50が硫黄であり、R55が水素である場合、式は「チオールカルボン酸」である。X50が硫黄であり、R56が水素である場合、式は「チオールホルメート」である。一方、X50が結合であり、R55が水素でない場合、上記式は「ケトン」基である。X50が結合であり、R55が水素である場合、上記式は「アルデヒド」基である。 The term “carboxyl” is known in the art and has the general formula:

Wherein X50 is a bond, or oxygen or sulfur, R55 and R56 are hydrogen, alkyl, alkenyl, — (CH ₂ ) _m —R61 or a pharmaceutically acceptable salt, and R56 is hydrogen , Alkyl, alkenyl or — (CH ₂ ) _m —R61, where m and R61 are as defined above]
The part which can be shown by is mentioned. Where X50 is an oxygen and R55 or R56 is not hydrogen, the formula is an “ester”. When X50 is oxygen and R55 is as defined above, the moiety is also referred to herein as a carboxyl group, especially when R55 is hydrogen, the formula is “carboxylic acid”. Where X50 is oxygen and R56 is hydrogen, the formula is “formate”. In general, where the oxygen atom of the above formula is replaced by sulfur, the formula is a “thiolcarbonyl” group. Where X50 is sulfur and R55 or R56 is not hydrogen, the formula is a “thiol ester”. Where X50 is sulfur and R55 is hydrogen, the formula is “thiol carboxylic acid”. Where X50 is sulfur and R56 is hydrogen, the formula is “thiolformate”. On the other hand, when X50 is a bond and R55 is not hydrogen, the above formula is a “ketone” group. Where X50 is a bond, and R55 is hydrogen, the above formula is an “aldehyde” group.

As used herein, the term “alkoxyl” or “alkoxy” means an alkyl group as defined above having an attached oxygen group. Typical alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like. “Ether” is two hydrocarbons covalently bonded by oxygen. Thus, alkyl substituents representing alkyl ethers are —O-alkyl, —O-alkenyl, —O-alkynyl, —O— (CH ₂ ) _m —R _8, where m and R ₈ are as defined above. Or similar to this.

［式中、R₄₁は電子対、水素、アルキル、シクロアルキルまたはアリールである］
で示すことができる部分が挙げられる。 The term “sulfonate” is known in the art and has the general formula:

[Wherein R ₄₁ is an electron pair, hydrogen, alkyl, cycloalkyl or aryl]
The part which can be shown by is mentioned.

  The terms trifuryl, tosyl, mesyl and nonafuryl are known in the art and refer to trifluoromethanesulfonyl, p-toluenesulfonyl, methanesulfonyl and nonafluorobutanesulfonyl groups, respectively. The terms triflate, tosylate, mesylate and nonaflate are known in the art and are trifluoromethanesulfonate ester, p-toluenesulfonate ester, methanesulfonate ester and nonafluorobutanesulfonate ester functional groups, respectively, and molecules containing these groups Means.

The term “carbamoyl” refers to —O (C═O) NRR ′ where R and R ′ are independently H, an aliphatic group, an aryl group, or a heteroaryl group.
The term “alkylamino” refers to —NHR where R is an alkyl group.
The term “dialkylamino” refers to —NRR ′ where R and R ′ are both alkyl groups.
The term “hydroxyalkyl” refers to —R—OH, where R is an aliphatic group.
The term “aminoalkyl” refers to —R—NH ₂ where R is an aliphatic group.
The term “alkylaminoalkyl” refers to —R—NH—R ′, where R and R ′ are both aliphatic groups.

The term “dialkylaminoalkyl” refers to —RN (R ′) — R ″, where R, R ′ and R ″ are aliphatic groups.
The term “arylaminoalkyl” refers to —R—NH—R ′, wherein R is an aliphatic group and R ′ is an aryl group.
The term “oxo” means a carbonyl oxygen (═O).

で示される基は二価アルキルまたはアルキルジラジカルであり；式：

で示される基もまた、二価アルキルまたはアルキルジラジカルであり；式：

で示される基は二価アリールまたはアリールジラジカルであり；式：

で示される基は二価アラルキルまたはアラルキルジラジカルであり；式：

で示される基は二価(アルキル)ヘテロアラルキルまたは(アルキル)ヘテロアラルキルジラジカルである。 As used herein, the terms “diradical” or “divalent” are used interchangeably and are derived from alkyl, alkenyl, alkynyl, alkylamino, alkoxyl, cycloalkyl, heterocycloalkyl, aryl, aralkyl, heterocyclyl, heteroaryl and heteroaralkyl groups. Any one of a series of divalent groups. For example, the formula:

The group represented by is a divalent alkyl or alkyl diradical;

The group represented by is also a divalent alkyl or alkyl diradical;

The group represented by is a divalent aryl or aryl diradical;

The group represented by is a divalent aralkyl or aralkyl diradical;

Is a divalent (alkyl) heteroaralkyl or (alkyl) heteroaralkyl diradical.

  The abbreviations Me, Et, Ph, Tf, Nf, Ts, Ms are methyl, ethyl, phenyl, trifluoromethanesulfonyl, nonafluorobutanesulfonyl, p-toluenesulfonyl and methanesulfonyl, respectively. A more comprehensive list of abbreviations utilized by organic chemists of ordinary skill can be found in the first issue of each volume of the Journal of Organic Chemistry; this list is typically shown in a table entitled Standard List of Abbreviations . Abbreviations are included in the list, and all abbreviations utilized by organic chemists of ordinary skill are incorporated herein by reference.

［式中、R₄₁は上記に定義されるとおりである］
で示すことができる部分が挙げられる。 The term “sulfate” is known in the art and has the general formula:

[Wherein R ₄₁ is as defined above]
The part which can be shown by is mentioned.

で示すことができる部分が挙げられる。
用語「スルファモイル」は当分野にて知られており、一般式：

で示すことができる部分が挙げられる。 The term “sulfonylamino” is known in the art and has the general formula:

The part which can be shown by is mentioned.
The term “sulfamoyl” is known in the art and has the general formula:

The part which can be shown by is mentioned.

［式中、R₄₄は水素、アルキル、アルケニル、アルキニル、シクロアルキル、ヘテロシクリル、アリールまたはヘテロアリールからなる群から選択される］
で示すことができる部分である。 As used herein, the term “sulfonyl” has the general formula:

Wherein R ₄₄ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl.
This is the part that can be shown.

［式中、R₄₄は水素、アルキル、アルケニル、アルキニル、シクロアルキル、ヘテロシクリル、アラルキルまたはアリールからなる群から選択される］
で示すことができる部分である。 As used herein, the term “sulfoxide” has the general formula:

Wherein R ₄₄ is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aralkyl or aryl.
This is the part that can be shown.

“Selenoalkyl” means an alkyl group having an attached substituted seleno group. Typical “selenoethers” that may be substituted on the alkyl are —Se-alkyl, —Se-alkenyl, —Se-alkynyl and —Se— (CH ₂ ) _m —R ₇ (where m and R ₇ is as defined above).

  Similar substitutions are made on alkenyl and alkynyl groups to produce, for example, aminoalkenyl, aminoalkynyl, amidoalkenyl, amidoalkynyl, iminoalkenyl, iminoalkynyl, thioalkenyl, thioalkynyl, carbonyl-substituted alkenyl or alkynyl.

  In this specification, the definition of each expression when it occurs more than once in any structure, such as alkyl, m, n, etc., is independent of the definitions elsewhere in the same structure.

  “Substitution” or “substitution with” refers to a stable compound in which such substitution is subject to substitution atoms and possible valences of substituents, and substitution is not spontaneously converted by, for example, rearrangement, cyclization, elimination, etc. It will be understood to include the implicit condition of bringing.

  As used herein, the term “substituted” is intended to include all permissible substituents of organic compounds. In a broad aspect, permissible substituents include acyclic and cyclic, branched and unbranched, carbocycles and heterocycles, aromatic and nonaromatic substituents of organic compounds. Exemplary substituents include, for example, those described herein. The permissible substituents can be one or more of the same or different for appropriate organic compounds. For the purposes of the present invention, a heteroatom such as nitrogen may have a hydrogen substituent and / or any permissible substituent of the organic compounds described herein that satisfy the valence of the heteroatom. it can. The present invention is not limited in any way by the permissible substituents of organic compounds.

As used herein, the term “protecting group” means a temporary substituent that protects a potentially reactive functional group from unwanted chemical transformations. Examples of such protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively. The field of protecting group chemistry has been reviewed (Greene, TW; Wuts, PGM Protective Groups in Organic Synthesis, 2 nd ed .; Wiley: New York, 1991). Protected forms of the compounds of the invention are included within the scope of the invention.

  Some compounds of the present invention may exist in particular geometric or stereoisomeric forms. The present invention covers all such cis- and trans-isomers, R- and S-enantiomers, diastereomers, (D) -isomers, (L) -isomers, racemic mixtures and other mixtures thereof. Compounds are included within the scope of the present invention. Additional asymmetric carbon atoms can be present in substituents such as alkyl groups. All such isomers as well as mixtures thereof are intended to be included in the present invention.

  For example, if a particular enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary group, separating the resulting diastereomeric mixture and cleaving the auxiliary group to produce pure The desired enantiomer is obtained. Alternatively, if the molecule contains a basic functional group such as amino or an acidic functional group such as carboxyl, a diastereomeric salt is formed with a suitable optically active acid or base, and the formed diastereomers are then transferred to the art. The pure enantiomer is recovered after resolution by well known fraction crystallization or chromatographic methods.

  Included equivalents of the above compounds include compounds that otherwise correspond to the same general characteristics (eg, function as analgesics), wherein one or more substituents are sigma Simple modifications are made so as not to adversely affect the effectiveness of the compound in binding to the receptor. In general, the compounds of this invention may be prepared using readily available starting materials, reagents and conventional synthetic procedures, for example, by the methods illustrated in the general reaction schemes as described below, or modifications thereof. Can do. In these reactions it is also possible to use variants known per se but not mentioned here.

  For the purposes of the present invention, chemical elements are identified according to the periodic table of elements, CAS version, Handbook of Chemistry and Physics, 67th Ed., 1986-87 front cover.

  As used herein, the term “subject” means an animal, typically a mammal or a human, for the purposes of treatment, observation and / or experimentation. When the term is used in conjunction with administration of a compound or drug, the subject is for the purpose of treatment, observation and / or administration of the compound or drug.

  As used herein, the term “therapeutically effective amount” refers to a biological or medical response (disease, condition or condition to be treated) in a cell culture, tissue system, animal or human that is sought by a researcher, veterinarian, clinician or physician. Means the amount of active compound or medicament that elicits the relief of the symptoms of the disorder). In the present invention, such an amount would be sufficient to bind to bcl-2 in the cell and inhibit at least part of the anti-apoptotic activity of the protein. Such an amount is sufficient to provide therapeutic efficacy in the patient, or can serve to make the cells sensitive to treatment with another anticancer agent.

  The term “composition” is intended to encompass products containing specific components in specific amounts, as well as any product that directly or indirectly results in a combination of specific components in specific amounts. .

  The term “pharmaceutically acceptable carrier” means a medium used to produce the desired dosage form of the compound. Pharmaceutically acceptable carriers include one or more solvents, diluents or other liquid vehicles; dispersants or suspension aids; surfactants; isotonic agents; thickeners or emulsifiers; preservatives; A lubricant and the like. The literature (Remington's Pharmaceutical Sciences, Fifteenth Edition, EW Martin (Mack Publishing Co., Easton, Pa., 1975) and Handbook of Pharmaceutical Excipients, Third Edition, AH Kibbe ed. (American Pharmaceutical Assoc. 2000)) Various carriers used in formulation and known techniques for their production are disclosed.

  The terms “Bcl-mediated disorder” and “disorder mediated by cells that express a Bcl protein” refer to pathologies and disease states in which the Bcl protein is involved. Such a role can be directly related to the pathological condition or indirectly related to the condition. A common feature of this class of pathology is that the pathology can be improved by inhibiting the Bcl protein or its associated activity or function.

  As used herein, the terms “Bcl” and “Bcl protein” refer to one or more Bcl-2 subfamily anti-apoptotic proteins Bcl-2, Bcl-w, Mcl-1, Bcl-XL, A1, Bfl1, Bcl-B. , Including BOO / DIVA and its homologues.

［式中、それぞれ独立して、
nは0、1、2、3または4であり；
R¹はそれぞれ独立してH、アルキル、アルケニル、アルキニル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、ヘテロアラルキル、ハライド、ヒドロキシル、アルコキシル、アリールオキシ、アシルオキシ、アミノ、アルキルアミノ、アリールアミノ、アシルアミノ、アラルキルアミノ、ニトロ、アシルチオ、カルボキサミド、カルボキシル、ニトリル、-COR⁵、-CO₂R⁵、-N(R⁵)CO₂R⁶、-OC(O)N(R⁵)(R⁶)、-N(R⁵)SO₂R⁶または-N(R⁵)C(O)N(R⁵)(R⁶)であり；
R²およびR³はそれぞれ独立してH、アルキル、アルケニル、アルキニル、アリール、アラルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリール、ヘテロアラルキルまたは-[C(R⁵)(R⁶)]_p-R⁴であるか；または式1a：

（式中、
mは0、1、2、3、4または5であり；
R⁷はそれぞれ独立してH、アルキル、アリール、アルケニル、ハライド、ヒドロキシル、アルコキシル、アルケニルオキシ、アリールオキシ、アシルオキシ、アミノ、アルキルアミノ、アリールアミノ、アシルアミノ、アラルキルアミノ、ニトロ、アシルチオ、カルボキサミド、カルボキシル、ニトリル、-OSO₃R⁵、-SO₂R⁵、-S(O)R⁵、-SR⁵、-PO₂OR⁵、-OPO₂OR⁵、-COR⁵、-CO₂R⁵、-OCH₂CO₂R⁵または-OCH₂C(O)N(R⁵)(R⁶)であるか；または2つのR⁷は一緒になって5-8の環原子の単環式環（該環原子の1、2または3の原子は独立してS、OまたはNである）を形成することができる）
で示される基を有し；
R⁴はハライド、ヒドロキシル、アルコキシル、アリールオキシ、アシルオキシ、アミノ、アルキルアミノ、アリールアミノ、アシルアミノ、アラルキルアミノ、ニトロ、アシルチオ、カルボキサミド、カルボキシル、ニトリル、-OSO₃R⁵、-SO₂R⁵、-S(O)R⁵、-PO₂OR⁵、-OPO₂OR⁵、-COR⁵、-CO₂R⁵、-N(R⁵)CO₂R⁶、-OC(O)N(R⁵)(R⁶)、-N(R⁵)SO₂R⁶または-N(R⁵)C(O)N(R⁵)(R⁶)であり；
R⁵およびR⁶はそれぞれ独立してH、アルキル、アルケニル、アルキニル、アリール、アラルキル、シクロアルキル、ヘテロシクリル、ヘテロシクリルアルキル、ヘテロアリールまたはヘテロアラルキルであるか；またはR⁵およびR⁶は一緒になって4-8の環原子の単環式環（該環原子の1、2または3の原子は独立してS、OまたはNである）を形成することができる］
で示される化合物またはその医薬的に許容される塩に関する。 Compounds of the Invention In some embodiments, the present invention provides compounds of formula 1:

[In the formula, each independently,
n is 0, 1, 2, 3 or 4;
Each R ¹ is independently H, alkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, halide, hydroxyl, alkoxyl, aryloxy, acyloxy, amino, alkylamino, arylamino, acylamino , aralkylamino, nitro, acylthio, carboxamide, carboxyl, _{^{nitrile, -COR 5, -CO 2 R 5}} , -N (R 5) CO 2 R 6, -OC (O) N (R 5) (R 6), It is _{^{-N (R 5) SO 2 R}} 6 or ^{-N (R 5) C (O} ) N (R 5) (R 6);
R ² and R ³ are each independently H, alkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl or — [C (R ⁵ ) (R ⁶ )] _p —R ⁴ Or is Formula 1a:

(Where
m is 0, 1, 2, 3, 4 or 5;
Each R ⁷ is independently H, alkyl, aryl, alkenyl, halide, hydroxyl, alkoxyl, alkenyloxy, aryloxy, acyloxy, amino, alkylamino, arylamino, acylamino, aralkylamino, nitro, acylthio, carboxamide, carboxyl, Nitrile, -OSO ₃ R ⁵ , -SO ₂ R ⁵ , -S (O) R ⁵ , -SR ⁵ , -PO ₂ OR ⁵ , -OPO ₂ OR ⁵ , -COR ⁵ , -CO ₂ R ⁵ , -OCH ₂ CO ₂ R ⁵ or —OCH ₂ C (O) N (R ⁵ ) (R ⁶ ); or two R ⁷ together are monocyclic rings of 5-8 ring atoms (the ring 1, 2 or 3 atoms can be independently S, O or N)
Having a group represented by:
R ⁴ is halide, hydroxyl, alkoxyl, aryloxy, acyloxy, amino, alkylamino, arylamino, acylamino, aralkylamino, nitro, acylthio, carboxamide, carboxyl, nitrile, -OSO ₃ R ⁵ , -SO ₂ R ⁵ ,- S (O) R ⁵ , -PO ₂ OR ⁵ , -OPO ₂ OR ⁵ , -COR ⁵ , -CO ₂ R ⁵ , -N (R ⁵ ) CO ₂ R ⁶ , -OC (O) N (R ⁵ ) (R ⁶ ), —N (R ⁵ ) SO ₂ R ⁶ or —N (R ⁵ ) C (O) N (R ⁵ ) (R ⁶ );
R ⁵ and R ⁶ are each independently H, alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroaralkyl; or R ⁵ and R ^{6 taken} together Can form a monocyclic ring of 4-8 ring atoms (1, 2 or 3 atoms of the ring atoms are independently S, O or N)]
Or a pharmaceutically acceptable salt thereof.

からなる群から選択される化合物にも関する。 The present invention also includes the following compounds:

Also relates to a compound selected from the group consisting of:

  Another aspect of the invention relates to a pharmaceutical composition comprising the above compound and at least one pharmaceutically acceptable excipient.

Methods of the Invention One aspect of the invention relates to a method of treating a Bcl-mediated disorder comprising administering a therapeutically effective amount of the above compound to a patient in need thereof.

  In certain embodiments, the present invention relates to the aforementioned method, wherein the Bcl-mediated disorder is cancer or a neoplastic disease.

  In some embodiments, the invention provides that the cancer or neoplastic disease is acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia, myeloblastic, promyelocytic, myelomonocytic, monocytic Erythroleukemia, chronic leukemia, chronic myeloid (granulocytic) leukemia, chronic lymphocytic leukemia, polycythemia vera, Hodgkin's disease, non-Hodgkin's disease; multiple myeloma, Waldenstrom's macroglobulinemia, severe Chain disease, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, angiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphatic endothelial sarcoma, synovial tumor, mesothelioma, Ewing tumor, leiomyosarcoma , Rhabdomyosarcoma, colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell cancer, basal cell cancer, adenocarcinoma, sweat gland cancer, sebaceous gland cancer, papillary cancer , Papillary adenocarcinoma, cystadenocarcinoma, medullary carcinoma , Bronchial cancer, renal cell cancer, liver cancer, bile duct cancer, choriocarcinoma, seminoma, embryonic cancer, Wilms tumor, cervical cancer, uterine cancer, testicular tumor, lung cancer, small cell Lung cancer, bladder cancer, epithelial cancer, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pineal tumor, hemangioblastoma, acoustic neuroma, oligodendroglioma, marrow The above method is selected from the group consisting of melanoma, melanoma, neuroblastoma, retinoblastoma and endometrial cancer.

  In some embodiments, the invention provides that the cancer is follicular lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, chronic lymphocytic leukemia prostate cancer, breast cancer, neuroblastoma, colorectal , Endometrium, ovary, lung cancer, hepatocellular carcinoma, multiple myeloma, head and neck cancer or testicular cancer.

In certain embodiments, the present invention relates to the aforementioned method, wherein the cancer overexpresses Bcl protein.
In certain embodiments, the present invention relates to the aforementioned method, wherein the cancer is dependent on Bcl protein for growth and survival.
In some embodiments, the present invention relates to the aforementioned method, wherein the Bcl protein is Bcl-2.
In some embodiments, the present invention relates to the aforementioned method, wherein the Bcl protein is Bcl-xL.
In certain embodiments, the present invention relates to the aforementioned method, wherein the cancer exhibits chromosomal translocation t (14; 18).

In certain embodiments, the present invention relates to the aforementioned method, wherein the compound is administered parenterally.
In certain embodiments, the present invention relates to the aforementioned method, wherein the compound is administered intramuscularly, intravenously, subcutaneously, orally, pulmonary, intrathecal, topically or intranasally.
In certain embodiments, the present invention relates to the aforementioned method, wherein the compound is administered systemically.
In certain embodiments, the present invention relates to the aforementioned method, wherein the patient is a mammal.
In certain embodiments, the present invention relates to the aforementioned method, wherein the patient is a primate.
In some embodiments, the present invention relates to the aforementioned method, wherein the patient is a human.

In another aspect, the invention relates to a method of treating a Bcl mediated disorder comprising administering to a patient in need thereof a therapeutically effective amount of a chemotherapeutic agent together with a therapeutically effective amount of the above compound.
In certain embodiments, the present invention relates to the aforementioned method, wherein the Bcl-mediated disorder is cancer or a neoplastic disease.

  In some embodiments, the invention provides that the cancer or neoplastic disease is acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia, myeloblastic, promyelocytic, myelomonocytic, monocytic Erythroleukemia, chronic leukemia, chronic myeloid (granulocytic) leukemia, chronic lymphocytic leukemia, polycythemia vera, Hodgkin's disease, non-Hodgkin's disease; multiple myeloma, Waldenstrom's macroglobulinemia, severe Chain disease, fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, chordoma, angiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphatic endothelial sarcoma, synovial tumor, mesothelioma, Ewing tumor, leiomyosarcoma , Rhabdomyosarcoma, colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell cancer, basal cell cancer, adenocarcinoma, sweat gland cancer, sebaceous gland cancer, papillary cancer , Papillary adenocarcinoma, cystadenocarcinoma, medullary cancer, bronchial cancer, Cell cancer, liver cancer, bile duct cancer, choriocarcinoma, seminoma, embryonic cancer, Wilms tumor, cervical cancer, uterine cancer, testicular tumor, lung cancer, small cell lung cancer, bladder cancer, Epithelial cancer, glioma, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pineal tumor, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, The above method is selected from the group consisting of neuroblastoma, retinoblastoma and endometrial cancer.

In certain embodiments, the present invention relates to the aforementioned method, wherein the cancer overexpresses Bcl protein.
In certain embodiments, the present invention relates to the aforementioned method, wherein the cancer is dependent on Bcl protein for growth and survival.
In some embodiments, the present invention relates to the aforementioned method, wherein the Bcl protein is Bcl-2.
In some embodiments, the present invention relates to the aforementioned method, wherein the Bcl protein is Bcl-xL.
In certain embodiments, the present invention relates to the aforementioned method, wherein the cancer exhibits chromosomal translocation t (14; 18).

In some embodiments, the invention is such that the amount of the compound described herein reduces the cellular level of Bcl client protein, and the amount of chemotherapeutic agent is reduced by the chemotherapeutic agent. It relates to the above method, which is such that it is effectively inhibited.
In certain embodiments, the present invention relates to the aforementioned method, wherein the compound is administered parenterally.
In certain embodiments, the present invention relates to the aforementioned method, wherein the compound is administered intramuscularly, intravenously, subcutaneously, orally, pulmonary, intrathecal, topically or intranasally.

In certain embodiments, the present invention relates to the aforementioned method, wherein the compound is administered systemically.
In certain embodiments, the present invention relates to the aforementioned method, wherein the patient is a mammal.
In certain embodiments, the present invention relates to the aforementioned method, wherein the patient is a primate.
In some embodiments, the present invention relates to the aforementioned method, wherein the patient is a human.

Pharmaceutical composition In another embodiment, the present invention comprises a therapeutically effective amount of one or more of the above compounds and is formulated with one or more pharmaceutically acceptable carriers (additives) and / or diluents, A pharmaceutically acceptable composition is provided. As described in detail below, the pharmaceutical compositions of the invention can be specifically formulated for administration in solid or liquid form, including those compatible with: (1) oral administration; For example drench (aqueous or non-aqueous solutions or suspensions), tablets, eg oral, sublingual and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) non Oral administration, eg, subcutaneously, intramuscularly, intravenously or by epidural injection, eg as a sterile solution or suspension or sustained release formulation; (3) topical application, eg cream, ointment or controlled release patch or skin As a spray; (4) intravaginally or rectally, eg as a pessary, cream or foam; (5) sublingual; (6) intraocular; (7) transdermal; (8) nasal cavity; (9) lung; Or (10) Within the sheath.

  As used herein, the term “therapeutically effective amount” is a compound that is effective to produce a desired therapeutic effect in at least a subpopulation of cells in an animal with a reasonable profit / loss ratio applicable to any medical treatment. Means the amount of the substance or the composition containing the compound of the present invention.

  As used herein, the term “pharmaceutically acceptable” refers to contact with human and animal tissues without excessive toxicity, irritation, allergic reactions or other problems or complications within the scope of sound medical judgment. Used to mean compounds, substances, compositions and / or dosage forms suitable for use in

  As used herein, the term “pharmaceutically acceptable carrier” refers to a liquid filler or solid filler that is involved in the transport or transport of a compound of interest from one organ or body part to another organ or body part. Pharmaceutically acceptable substances, compositions such as agents, diluents, excipients, manufacturing aids (eg lubricants, talc, magnesium stearate, calcium or zinc, or stearic acid) or solvent encapsulated substances Or vehicle. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation but not injurious to the patient. Examples of substances that can serve as pharmaceutically acceptable carriers include: (1) sugars such as lactose, glucose and sucrose; (2) starches such as corn starch and potato starch; (3) sodium carboxymethylcellulose, ethylcellulose and acetic acid (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppository wax; (9) peanuts Oils such as oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) oleic acid Esters such as ethyl and ethyl laurate; 13) Agar; (14) Buffering agents such as magnesium hydroxide and aluminum hydroxide; (15) Alginic acid; (16) Pyrogen-free water; (17) Isotonic saline; (18) Ringer's solution; (19) Ethyl (20) pH buffer solutions; (21) polyesters, polycarbonates and / or polyanhydrides; and (22) other non-toxic compatible materials used in pharmaceutical formulations.

  As noted above, some embodiments of the compounds of the present invention may contain a basic functional group such as amino or alkylamino and are therefore pharmaceutically acceptable salts with pharmaceutically acceptable acids. Can be formed. In this regard, the term “pharmaceutically acceptable salts” refers to inorganic and organic acid addition salts of the compounds of the invention that are relatively non-toxic. These salts are prepared in the system during the manufacturing process of the administration vehicle or dosage form, or the free base form of the pure compound of the present invention is reacted separately with a suitable organic or inorganic acid for subsequent purification. It can be prepared by isolating the salt formed therein. Typical salts include hydrobromide, hydrochloride, sulfate, hydrogen sulfate, phosphate, nitrate, acetate, valerate, oleate, palmitate, stearate, lauric acid Salt, benzoate, lactate, phosphate, tosylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate and laurylsulfonate salt (See, for example, Berge et al. (1977) “Pharmaceutical Salts”, J. Pharm. Sci. 66: 1-19).

  Pharmaceutically acceptable salts of the subject compounds include the conventional non-toxic salts or quaternary ammonium salts of the compounds, such as non-toxic organic or inorganic acids. For example, such conventional non-toxic salts include salts derived from inorganic acids such as hydrochloride, hydrobromide, sulfate, sulfamate, phosphate, nitrate; and acetate, propionate, succinate , Glycolate, stearate, lactate, malate, tartrate, citrate, ascorbate, palmitate, maleate, hydroxymaleate, phenylacetate, glutamate, benzoate Manufactured from organic acids such as acid salt, salicylate, sulfanilate, 2-acetoxybenzoate, fumarate, toluenesulfonate, methanesulfonate, ethanedisulfonate, oxalate, isothionate Salt.

  In other cases, the compounds of the present invention can contain one or more acidic functional groups and can form pharmaceutically acceptable salts with pharmaceutically acceptable bases. In this case, the term “pharmaceutically acceptable salt” is a relatively non-toxic inorganic and organic base addition salt of the compounds of the invention. These salts can also be produced in the system in the process of making the administration vehicle or dosage form, or the free acid form of the pure compound can be converted to a pharmaceutically acceptable metal cation hydroxide, carbonate or carbonate. It can be prepared by reacting separately with a suitable base such as a hydrogen salt, ammonia or a pharmaceutically acceptable organic primary, secondary or tertiary amine. Typical alkali or alkaline earth salts include lithium, sodium, potassium, calcium, magnesium, and aluminum salts. Typical organic amines useful for the formation of base addition salts include ethylamine, diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like (see, eg, Berge et al. Above).

  Wetting agents such as sodium lauryl sulfate and magnesium stearate, emulsifiers and lubricants and colorants, mold release agents, coating agents, sweeteners, flavors and fragrances, preservatives and antioxidants are also present in the composition. be able to.

  Examples of pharmaceutically acceptable antioxidants include: (1) water-soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium hydrogensulfate, sodium hydrogensulfate, sodium sulfite; (2) ascorbyl palmitate, Oil-soluble antioxidants such as butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol; and (3) citric acid, ethylenediaminetetraacetic acid (EDTA), sorbitol, tartaric acid, Examples include metal chelating agents such as phosphoric acid.

  Formulations of the present invention include those suitable for oral, nasal, topical (such as buccal and sublingual), rectal, vaginal and / or parenteral administration. The formulations are preferably given in unit dosage form and can be prepared by any method well known in the pharmaceutical arts. The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated, the particular form of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound that produces a therapeutic effect. Generally, this amount will range from about 0.1 percent to about 99 percent, preferably from about 5 percent to about 70 percent, and most preferably from about 10 percent to about 30 percent of the active ingredient in 100 percent.

  In some embodiments, the formulations of the present invention comprise an excipient selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle forming agents such as bile acids and polymeric carriers such as polyesters and polyanhydrides; Including the compound of the present invention. In some embodiments, the formulation refers to a compound of the present invention that can be administered orally.

  The method for producing these preparations or compositions includes a step of bringing the compound of the present invention into contact with a carrier and optionally one or more auxiliary components. In general, formulations are prepared by uniformly and intimately contacting a compound of the present invention with a liquid carrier or a fragmented solid carrier or both and then, if necessary, shaping the product.

  Formulations of the present invention suitable for oral administration include liquids in capsules, cachets, pills, tablets, lozenges (using flavor bases, usually sucrose and acacia or tragacanth), powders, granules, or aqueous or non-aqueous liquids In the form of a suspension, or oil-in-water or water-in-oil liquid emulsion, or elixir or syrup, or troche (using gelatin and glycerin or inert bases such as sucrose and acacia), and / or as a mouthwash Each containing a defined amount of the compound of the present invention as an active ingredient. The compound of the present invention can also be administered as a bolus, electuary or paste.

  In solid dosage forms of the present invention (capsules, tablets, pills, dragees, powders, granules, troches, etc.) for oral administration, the active ingredient is one or more pharmaceutically such as sodium citrate or dicalcium phosphate Mixed with an acceptable carrier and / or any of the following: (1) a filler or bulking agent such as starch, lactose, sucrose, glucose, mannitol and / or silicic acid; (2) eg carboxymethylcellulose, alginate Binders such as gelatin, polyvinylpyrrolidone, sucrose and / or acacia; (3) humectants such as glycerol; (4) agar-agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain silicates and carbonates Disintegrants such as sodium; (5) Elution retarders such as paraffin; (6) Quaternary ammo Absorption promoters such as surfactants such as um compounds and polyxamers and sodium lauryl sulfate; (7) wetting agents such as cetyl alcohol, glycerol monostearate and nonionic surfactants; (8) kaolin and bentonite clays, etc. (9) Lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycol, sodium lauryl sulfate, zinc stearate, sodium stearate, stearic acid and mixtures thereof; (10) colorants; and (11) Controlled release agent such as crospovidone or ethylcellulose. In the case of capsules, tablets and pills, the pharmaceutical composition can also contain buffering agents. Similar types of solid compositions can also be used as fillers in soft and hard shell gelatin capsules using excipients such as lactose or lactose and high molecular weight polyethylene glycols.

  A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be made with binders (eg gelatin or hydroxypropylmethylcellulose), lubricants, inert diluents, preservatives, disintegrants (eg sodium starch glycolate or crosslinked sodium carboxymethylcellulose), surfactants or dispersants. Can be manufactured. Molded tablets can be made by molding in a suitable device a mixture of the powdered compound moistened with an inert liquid diluent.

  Tablets of the pharmaceutical composition of the present invention, and other solid dosage forms such as sugar-coated tablets, capsules, pills, and granules are suitably coated and external such as enteric coatings and other coatings well known in the pharmaceutical formulation field. It may be obtained with a structure or manufactured. They can also be formulated to provide delayed or controlled release of the active ingredient therein using, for example, hydroxypropyl methylcellulose in variable proportions to provide the desired release profile, other polymer matrices, liposomes and / or microspheres. Can also be provided. They can be formulated for rapid release, eg lyophilization. They can be sterilized, for example, by filtration through a bacteria-retaining filter, or by incorporating a sterilant in sterile water or some other sterile injectable medium in the form of a sterile solid composition that can be dissolved immediately before use. can do. These compositions may also contain opacifiers as appropriate, and may be compositions that release only the active ingredient or optionally delayed in certain portions of the gastrointestinal tract. Examples of embedding compositions that can be used include polymeric substances and waxes. The active ingredient can also be in microencapsulated form, if necessary, with one or more of the above-described excipients.

  Liquid dosage forms for oral administration of the compounds of the present invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, liquid dosage forms are inert diluents commonly used in the art, such as water or other solvents, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, Propylene glycol, 1,3-butylene glycol, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil and sesame oil), glycerol, tetrahydrofuryl alcohol, fatty acid esters of polyethylene glycol and sorbitan, and mixtures thereof Solubilizers and emulsifiers.

  In addition to inert diluents, oral compositions can also include adjuvants such as wetting agents, emulsifying agents and suspending agents, sweetening, flavoring, coloring, flavoring and preserving agents.

  In addition to the active compound, suspensions can be suspended, such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof. Suspending agents can be included.

  Formulations for rectal or vaginal administration of the pharmaceutical composition of the invention comprise one or more suitable nonirritating excipients comprising one or more compounds of the invention, for example cocoa butter, polyethylene glycol, suppository wax or salicylate. Or can be prepared by mixing with a carrier and can be presented as a suppository that is solid at room temperature but liquid at body temperature and therefore melts in the rectum or vaginal cavity to release the active compound .

  Formulations of the present invention suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing a carrier as known to be suitable in the art. It is done.

  Dosage forms for topical or transdermal administration of the compounds of the present invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants. The active compound can be mixed under sterile conditions with a pharmaceutically acceptable carrier, and any preservatives, buffers, or propellants that may be required.

  Ointments, pastes, creams and gels contain animal and vegetable fats, oils, waxes, paraffins, starches, tragacanth, cellulose derivatives, polyethylene glycol, silicon, bentonite, silicic acid, talc, in addition to the active compounds of the invention. And excipients such as zinc oxide or mixtures thereof.

  Powders and sprays can contain, in addition to the present compounds, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder or mixtures of these substances. The spray can further include conventional propellants such as chlorofluorohydrocarbons, and volatile unsubstituted hydrocarbons such as butane and propane.

  Transdermal patches further have the advantage of providing controlled delivery of the compounds of the present invention to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. Such flow rate can be controlled by providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

  Ophthalmic formulations, ointments, powders, solutions and the like are also encompassed within the scope of the present invention.

  Pharmaceutical compositions of the present invention suitable for parenteral administration comprise one or more pharmaceutically acceptable sterile isotonic aqueous or non-aqueous that can be reconstituted in a sterile injectable solution or dispersion just prior to use. Contains one or more compounds of the present invention together with a solution, dispersion, suspension or emulsion, or sterile powder, and is a sugar, alcohol, antioxidant, buffer, bacteriostatic agent, target receptor blood isotonic formulation The solute provided, or a suspending or thickening agent can be included.

  Examples of suitable aqueous and non-aqueous carriers that can be used in the pharmaceutical compositions of the present invention include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol) and suitable mixtures thereof, vegetable oils such as olive oil, And injectable organic esters such as ethyl oleate. The proper fluidity can be maintained, for example, by the use of a coating material such as lecithin, by the maintenance of the required particle size during dispersion and by the use of surfactants.

  These compositions can also contain adjuvants such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms on the target compound can be ensured by including various antibacterial and antifungal agents such as parabens, chlorobutanol, phenol sorbic acid and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, in the composition. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.

  In some cases it is desirable to delay the absorption of the drug from subcutaneous or intramuscular injection in order to prolong the effect of the drug. This can be achieved by using crystalline or amorphous liquid suspensions with low water solubility. The absorption rate of the drug then depends on its dissolution rate and may depend on the crystal size and crystal form as well. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.

  Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions that are compatible with body tissues.

  When the compound of the present invention is administered to humans and animals as a medicine, as a pharmaceutical composition containing, for example, 0.1 to 99% (more preferably 10 to 30%) of the active ingredient together with a pharmaceutically acceptable carrier. Can be given.

  The formulations of the present invention can be given orally, parenterally, topically, or rectally. They are of course given in a form suitable for each route of administration. For example, they are administered in tablet or capsule form by injection, inhalation, ophthalmic lotion, ointment, suppository, etc., by injection, infusion or inhalation administration; topically by lotion or ointment; and rectal by suppository. The Oral administration is preferred.

  As used herein, the terms “parenteral administration” and “parenteral administration” refer to administration forms other than enteral and topical administration, usually by injection, intravenous, intramuscular, intraarterial, sheath. Injections and infusions, including intra, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, epidermal, intraarticular, subcapsular, subarachnoid, intrathecal and intrasternal It is not limited to.

  As used herein, the terms “systemic administration”, “systemic administration”, “peripheral administration” and “peripheral administration” enter the patient's system and thus undergo metabolism and other steps such as subcutaneous administration. Mean administration of a compound, drug or other substance other than direct administration to the central nervous system.

  These compounds are for treatment by any suitable route of administration, such as oral, e.g. nasal, rectal, intravaginal, parenteral, intracapsular and topical, powders such as buccal and sublingual, ointments or drops Can be administered to humans and other animals.

  Regardless of the route of administration selected, the compounds of the present invention and / or the pharmaceutical compositions of the present invention that can be used in an appropriate hydrated form are pharmaceutically acceptable by conventional methods known to those skilled in the art. Into a dosage form.

  The actual dosage level of the active ingredient in the pharmaceutical composition of the present invention is such that the amount, composition and dosage form of the active ingredient are sufficient to achieve the desired therapeutic response for a particular patient without toxicity to the patient. Can change to get.

  The selected dose level will depend on the activity of the particular compound of the invention used or its ester, salt or amide, route of administration, administration time, rate of excretion or metabolism of the particular compound used, rate and extent of absorption, treatment Well-known in the medical field such as duration, other drugs, compounds and / or substances used in combination with the particular compound used, age, sex, weight, pathology, general health and medical history of the patient being treated It will depend on various factors.

  A physician or veterinarian having ordinary knowledge in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required. For example, a physician or veterinarian can lower the dosage of a compound of the present invention used in the pharmaceutical composition to a level lower than necessary to achieve the desired therapeutic effect and to gradually increase the dosage until the desired effect is achieved. You can start with.

  In general, a suitable daily dose of a compound of the invention will be that amount of the compound that is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend on the above factors. In general, when used for the indicated analgesic effect, oral, intravenous, intraventricular and subcutaneous doses of the compounds of the invention for patients will range from about 0.0001 to about 100 mg / kg body weight / day.

  If desired, the effective daily dose of the active compound can be administered in appropriate unit dosage forms as 2, 3, 4, 5, 6 or more sub-doses separately at appropriate intervals throughout the day. A preferred dose is 1 dose / day.

  When the compound of the present invention can be administered alone, it is preferable to administer the compound as a pharmaceutical preparation (composition).

  The compounds of the invention can be formulated for administration in any advantageous manner for use in human or veterinary medicine by analogy with other medicines.

  In another embodiment, the invention provides a pharmaceutically acceptable agent comprising a therapeutically effective amount of one or more of the subject compounds formulated with one or more pharmaceutically acceptable carriers (additives) and / or diluents. The composition is provided. As described in detail below, the pharmaceutical compositions of the invention can be specifically formulated for administration in solid or liquid form as adapted to: (1) oral administration; Eg drench (aqueous or non-aqueous solution or suspension), tablets, boluses, powders, granules, paste for tongue application; (2) parenteral administration, eg as sterile solutions or suspensions eg subcutaneous, intramuscular or intravenous By injection; (3) topical application, eg as a cream, ointment or spray applied to the skin, lungs or mucous membranes; or (4) vaginal or rectal, eg as a pessary, cream or foam; (5) tongue (6) intraocular; (7) transdermal; or (8) nasal cavity.

The term “treatment” also encompasses prevention, treatment and cure.
Patients receiving this treatment are any animals in need, such as primates, especially humans, and other mammals such as horses, cows, pigs and sheep; and generally poultry and pets.

  The compounds of the present invention can be administered as such or with a pharmaceutically acceptable carrier, and can also be administered with antibacterial agents such as penicillins, cephalosporins, aminoglycosides and glycopeptides. Thus, binding treatment includes sequential, simultaneous and separate administration of the active compound such that when the second administration is made, the first administration does not completely eliminate the therapeutic effect.

  The addition of the active compounds of the invention to the animal feed is preferably achieved by preparing a suitable premixed feed containing the active compound in an effective amount and incorporating the premix into the complete feed.

  Alternatively, an intermediate concentrate or supplementary feed containing the active ingredient can be mixed into the feed. Methods in which such premixed and complete feeds can be produced and administered are described in the literature (eg “Applied Animal Nutrition”, WH Freedman and CO., San Francisco, USA, 1969 or “Livestock Feeds and Feeding "O and B books, Corvallis, Ore., USA, 1977).

Micelle In recent years, the pharmaceutical industry has introduced microemulsification technology to improve the bioavailability of some lipophilic (water-insoluble) drugs. Examples include Trimetrine (Dordunoo, SK, et al., Drug Development and Industrial Pharmacy, 17 (12), 1685-1713, 1991 and REV 5901 (Sheen, PC, et al., J Pharm Sci 80 (7), 712-714, 1991) Among other things, microemulsification provides enhanced bioavailability by preferentially absorbing into the lymphatic system instead of the circulatory system, thereby avoiding the liver. Prevent destruction of compounds in the hepatobiliary circulation.

  While all suitable amphiphilic carriers are included, currently preferred carriers are generally those having a generally recognized safety (GRAS) state, where the solution is in a complex aqueous phase (eg, human gastrointestinal tract). The compound of the present invention can be solubilized and finely emulsified at a later stage when it starts to come into contact. Usually, amphiphilic components that meet these requirements have an HLB (Hydrophilic vs. Lipophilic Balance) value of 2-20, and the structure contains linear aliphatic groups in the range of C-6 to C-20. Including. For example, polyethylene-glycolized fatty glycerides and polyethylene glycols.

  Commercially available amphiphilic carriers are in particular the Gelucire series, Labrafil, Labrasol or Lauroglycol (all manufactured and distributed by Gattefosse Corporation, Saint Priest, France), PEG-monooleate, PEG-diolate, PEG-mono Including laurate and dilaurate, lecithin, polysorbate 80 (produced and distributed by the USA and many companies around the world).

Polymers Hydrophilic polymers suitable for use in the present invention are readily soluble in water, can be covalently attached to vesicle-forming lipids, and are resistant in vivo without toxic effects (ie, biocompatible). There is. Suitable polymers include polyethylene glycol (PEG), polylactic acid (also referred to as polylactide), polyglycolic acid (also referred to as polyglycolide), polylactic acid-polyglycolic acid copolymer and polyvinyl alcohol. Preferred polymers are those having a molecular weight of from about 100 or 120 daltons to about 5,000 or 10,000 daltons, more preferably from about 300 daltons to about 5,000 daltons. In a particularly preferred embodiment, the polymer is polyethylene glycol having a molecular weight of about 100 to about 5,000 daltons, more preferably about 300 to about 5,000 daltons. In a particularly preferred embodiment, the polymer is 750 Daltons polyethylene glycol (PEG (750)). A polymer can also be defined by its number of monomers; a preferred embodiment of the present invention uses a polymer of at least about 3 monomers, such as a PEG polymer consisting of 3 monomers (about 150 Daltons).

Other hydrophilic polymers that may be suitable for use in the present invention include polyvinylpyrrolidone, polymethoxazoline, polyethyloxazoline, polyhydroxypropylmethacrylamide, polymethacrylamide, polydimethylacrylamide, and derivatives such as hydroxymethylcellulose or hydroxyethylcellulose And cellulose.
In some embodiments, the formulations of the present invention comprise polyamides, polycarbonates, polyalkylenes, acrylic and methacrylic ester polymers, polyvinyl polymers, polyglycolides, polysiloxanes, polyurethanes and copolymers thereof, cellulose, polypropylene, polyethylene, Polystyrene, lactic acid and glycolic acid polymers, polyanhydrides, poly (ortho) esters, poly (butyric acid), poly (valeric acid), poly (lactide-co-caprolactone), polysaccharides, proteins, polyhyaluronic acid, polycyanoacrylate, And biocompatible polymers selected from the group consisting of fusions, mixtures or copolymers thereof.

Cyclodextrins Cyclodextrins are cyclic oligosaccharides composed of 6, 7 or 8 glucose units designated by the Greek letters alpha, beta or gamma, respectively. The presence of cyclodextrins with less than 6 glucose units is not known. Glucose units are linked by alpha-1,4-glucoside bonds. As a result of the chair-type conformation of the sugar unit, all secondary hydroxyl groups (C-2, C-3 positions) are on one side of the ring, but all primary hydroxyl groups at the C-6 position are opposite On the side. As a result, it is hydrophilic on the surface that makes cyclodextrin water-soluble. On the other hand, cyclodextrin cavities are hydrophobic because they are connected by hydrogen and ether-like oxygen at the C-3 and C-5 atoms. These matrices allow complexation with a variety of relatively hydrophobic compounds including, for example, steroidal compounds such as 17.beta.-estradiol (eg van Uden et al. Plant Cell Tiss. Org. Cult. 38: 1-3-113 (1994)). Complexation occurs through van der Waals interactions and hydrogen bond formation. For a general review of the chemistry of cyclodextrins, see the literature (Wenz, Agnew. Chem. Int. Ed. Engl., 33: 803-822 (1994)).

  The physicochemical properties of cyclodextrin derivatives strongly depend on the type and degree of substitution. For example, their solubility in water ranges from insoluble (eg triacetyl-beta-cyclodextrin) to 147% soluble (w / v) (G-2-beta-cyclodextrin). Furthermore, they are soluble in many organic solvents. The properties of cyclodextrins allow control over the solubility of various formulation ingredients by increasing or decreasing their solubility.

  Many cyclodextrins and their methods of manufacture have been described. For example, Parmeter (I) et al. (US Pat. No. 3,453,259) and Gramera et al. (US Pat. No. 3,457,731) disclosed electrically neutral cyclodextrins. Other derivatives include cyclodextrins with cationic properties [Parmeter (II), US Pat. No. 3,453,257], insoluble crosslinked cyclodextrins (Solms, US Pat. No. 3,420,788) and cyclodextrins with anionic properties [Parmeter ( III), US Patent No. 3,426,011]. Among cyclodextrin derivatives having anionic properties, carboxylic acid, phosphorous acid, phosphinic acid, phosphonic acid, phosphoric acid, thiophosphonic acid, thiosulfinic acid and sulfonic acid are bound to the parent cyclodextrin [see above Parmeter (See (III)). In addition, sulfoalkyl ether cyclodextrin derivatives are described by Stella et al. (US Pat. No. 5,134,127).

Liposomes Liposomes consist of at least one lipid bilayer cell membrane containing an aqueous intracellular compartment. Liposomes can be characterized by cell membrane type and size. Small unilamellar vesicles (SUVs) have a single cell membrane and typically range in diameter from 0.02 to 0.05 μm; large unilamellar vesicles (LUVS) are typically greater than 0.05 μm. Large oligolamellar vesicles and multilamellar vesicles have multiple normally concentric cell membrane layers, typically larger than 0.1 μm. Liposomes with several non-concentric cell membranes, ie some small vesicles contained within larger vesicles, are referred to as multivesicular vesicles.

  One embodiment of the present invention relates to a preparation comprising a liposome containing the compound of the present invention, wherein the liposome membrane is formulated to provide a liposome having an increased transport amount. Alternatively or additionally, the compound of the invention may be contained within or adsorbed onto the liposome bilayer of the liposome. The compound of the present invention aggregates with a lipid surfactant and can be transported into the internal space of the liposome; in such a case, the liposome membrane is formulated to resist the disruptive effect of the active agent-surfactant aggregate Have

  According to one specific embodiment of the present invention, the lipid bilayer of the liposome extends from the internal surface of the lipid bilayer to the internal space where the polyethylene glycol (PEG) chain is encapsulated by the liposome, and from the outside of the lipid bilayer. Includes lipids derivatized with PEG to extend to the surrounding environment.

  The active agent contained within the liposomes of the present invention is a solubilized form. Aggregates of surfactant and active agent (such as emulsions or micelles containing the active agent in question) can be incorporated into the interior space of the liposomes of the present invention. Surfactants include biocompatible lysophosphatidylcholine (LPC) that acts to disperse and solubilize the active agent and vary in chain length (eg, from about C.sub.14 to about C.sub.20), It can be selected from any suitable aliphatic, cycloaliphatic or aromatic surfactant, without being limited thereto. Polymer derivatized lipids such as PEG-lipids also act to inhibit micelle / cell membrane fusion, and the addition of polymers to surfactant molecules reduces the CMC of the surfactant and aids in micelle formation. It can be used for. Preferably, a surfactant having a CMC in the micromolar range; a higher CMC surfactant can be utilized to produce micelles incorporated into the liposomes of the present invention, but micelle surfactant monomers May affect liposome bilayer stability and may be a factor in designing liposomes of the desired stability.

  The liposomes of the present invention can be produced by any of a variety of techniques known in the art. For example, US Patent No. 4,235,871; International Published PCT Application WO 96/14057; New RRC, Liposomes: A practical approach, IRL Press, Oxford (1990), pages 33-104; Lasic DD, Liposomes from physics to applications, Elsevier Science Publishers BV , Amsterdam, 1993.

  For example, the liposomes of the present invention can be obtained by diffusing lipids derivatized with a hydrophilic polymer into preformed liposomes at a lipid concentration corresponding to the final mole percent of derivatized lipid desired in the liposome. For example, it can be produced by exposing preformed liposomes to micelles composed of lipid-grafted polymers. Liposomes containing hydrophilic polymers can also be formed by homogenization, lipid domain hydration or extrusion techniques, as is known in the art.

  In some embodiments of the invention, liposomes are produced to have a substantially homogeneous size in the selected size range. One effective sizing method involves extruding an aqueous suspension of liposomes through a series of polycarbonate membranes having a uniform pore size selected; the pore size of the cell membrane is generated by extrusion through the membrane. Will roughly correspond to the maximum size of liposomes. See, for example, US Pat. No. 4,737,323 (Apr. 12, 1988).

Release modifiers The release characteristics of the formulations of the present invention depend on the encapsulating material, the concentration of the encapsulated drug and the presence of the release modifier. For example, release can be handled in a pH dependent manner and can be the use of a pH sensitive coating that is released only at a lower pH such as the stomach or at a higher pH such as the intestine. An enteric coating can be used to prevent release that occurs until after passage through the stomach. Multiple coatings or mixtures of cyanamide encapsulated in different materials can be used to obtain an initial release in the stomach followed by a later release in the intestine. Release can also be accomplished by inclusion of a salt or pore former, which can increase water uptake or drug release by diffusion from the capsule. Excipients that modify the solubility of the drug can also be used to control the release rate. Agents that enhance matrix disintegration or release from the matrix can also be incorporated. They can be added to the drug as a separate phase (ie, microparticles) or co-dissolved in the polymer phase depending on the compound. In all cases, the amount should be between 0.1 and 30 percent (w / w polymer). Disintegration enhancer types include inorganic salts such as ammonium sulfate and ammonium chloride, organic acids such as citric acid, benzoic acid and ascorbic acid, inorganic bases such as sodium carbonate, potassium carbonate, calcium carbonate, zinc carbonate and zinc hydroxide, Examples include organic bases such as protamine sulfate, spermine, choline, ethanolamine, diethanolamine and triethanolamine, and surfactants such as Tween® and Pluronic®. A pore-forming agent (ie, a water-soluble compound such as an inorganic salt and sugar) that adds the microstructure to the matrix is added as fine particles. The range should be 1-30 percent (w / w polymer).

  Uptake can also be manipulated by changing the residence time of the particles in the intestine. This can be accomplished, for example, by coating the particles with an encapsulating material, a mucoadhesive polymer, or selecting as such. Examples include most polymers with free carboxyl groups such as chitosan, cellulose, especially polyacrylates (where polyacrylate means a polymer containing acrylate groups and modified acrylate groups such as cyanoacrylates and methacrylates). It is done.

The invention has been described generally and will be more readily understood by reference to the following examples, which are included solely for the purposes of illustration of certain embodiments and specific embodiments of the invention, and It is not limited.

パートA

3-ヨードベンズアルデヒド2（5.8 g, 25 mmol, 1 eq）のMeOH/THF（40 mL, 3:1）溶液に、NH₂OH・HClの水溶液（2.04 g, 29.5 mmol, 1.2 eq, 水10 mL中）を加えた。6 N KOHを用いてpHを9に調節した。反応物を室温にて2時間撹拌し、NaCNBH₃（1.5 g, 25 mmol, 1 eq）、次いでメチルオレンジの結晶を加えた。pH 2を2に調節し、得られた真紅色物質を1 N HClの添加反応中維持した。2時間後、NaCNBH₃の別の一部（1.5 g, 25 mmol, 1 eq）を加えた。混合物を14時間撹拌し、この時点にて溶媒の2/3を留去し、6 N KOH水溶液を加えてpHを9-10に上昇させた。この混合物をDCM（3 x 100 mL）で抽出した。有機層を集め、水、次いで食塩水で洗浄した。有機層をMgSO₄で乾燥し、ろ過し、減圧留去して灰白色固体として3を5.7 g得た。85%収率。 Example 1

Part A

To a solution of 3-iodobenzaldehyde 2 (5.8 g, 25 mmol, 1 eq) in MeOH / THF (40 mL, 3: 1), an aqueous solution of NH ₂ OH · HCl (2.04 g, 29.5 mmol, 1.2 eq, water 10 mL) Medium) was added. The pH was adjusted to 9 using 6 N KOH. The reaction was stirred at room temperature for 2 h and NaCNBH ₃ (1.5 g, 25 mmol, 1 eq) was added followed by methyl orange crystals. The pH 2 was adjusted to 2 and the resulting crimson material was maintained during the 1 N HCl addition reaction. After 2 hours, another portion of NaCNBH ₃ (1.5 g, 25 mmol, 1 eq) was added. The mixture was stirred for 14 hours, at which point 2/3 of the solvent was distilled off and 6 N KOH aqueous solution was added to raise the pH to 9-10. The mixture was extracted with DCM (3 x 100 mL). The organic layer was collected and washed with water followed by brine. The organic layer was dried over MgSO ₄ , filtered and evaporated under reduced pressure to give 5.7 g of 3 as an off-white solid. 85% yield.

N-(3-ヨードベンジル)ヒドロキシルアミン3（16 g, 64 mmol, 1 eq）のベンゼン320 mL溶液に、メチルグリオキシレート（6.8 g, 80 mmol, 1.25 eq）を加えた。Dean Starkトラップを用いて混合物を120℃まで3時間加熱した。溶液を室温まで冷却し、溶媒を減圧濃縮し、黄色固体として4を19.1 g得た。93%収率。 Part B

Methyl glyoxylate (6.8 g, 80 mmol, 1.25 eq) was added to a 320 mL benzene solution of N- (3-iodobenzyl) hydroxylamine 3 (16 g, 64 mmol, 1 eq). The mixture was heated to 120 ° C. for 3 hours using a Dean Stark trap. The solution was cooled to room temperature, and the solvent was concentrated under reduced pressure to obtain 19.1 g of 4 as a yellow solid. 93% yield.

ビス(2,2,2-トリフルオロエチル)ホスホノ酢酸メチルエステル5（28 g, 0.1 mmol, 1 eq）および18-クラウン-6（132 g, 0.50 mmol, 5 eq）のTHF 2 L溶液を窒素雰囲気下-78℃まで冷却した。冷却した溶液にカリウムビス(トリメチルシリル)アミド（20 g, 0.6 Mトルエン0.1 mmol中, 1 eq）を加えた。次いで(S)-2-(テトラヒドロピラニルオキシ)プロパノール6（J. Chem. Soc., Perkin. Trans. 1, 1994, 2791に記載のように合成; 16 g, 0.1 mmol, 1 eq）を加え、得られた混合物を30分間-78℃にて撹拌した。次いで飽和NH₄Cl水溶液を加え、生成物をエーテル（3×500 mL）で抽出した。有機相を集め、Na₂SO₄で乾燥し、ろ過し、減圧濃縮した。粗製物をシリカゲルクロマトグラフィーにより精製し、油状物13（13.5 g）を得た。63%収率。 Part C

A solution of bis (2,2,2-trifluoroethyl) phosphonoacetic acid methyl ester 5 (28 g, 0.1 mmol, 1 eq) and 18-crown-6 (132 g, 0.50 mmol, 5 eq) in THF 2 L Cooled to -78 ° C under atmosphere. To the cooled solution was added potassium bis (trimethylsilyl) amide (20 g, 0.6 M in 0.1 mmol of toluene, 1 eq). Then (S) -2- (tetrahydropyranyloxy) propanol 6 (synthesized as described in J. Chem. Soc., Perkin. Trans. 1, 1994, 2791; 16 g, 0.1 mmol, 1 eq) was added. The resulting mixture was stirred at −78 ° C. for 30 minutes. Saturated aqueous NH ₄ Cl was then added and the product was extracted with ether (3 × 500 mL). The organic phase was collected, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography to give oil 13 (13.5 g). 63% yield.

4(S)-(テトラヒドロ-ピラン-2-イルオキシ)-ペンタ-2-エン酸メチルエステル7（10 g, 46.7 mmol, 1 eq）をJ. Chem. Soc., Perkin. Trans. 1, 1994, 2791記載の手順に従い、DIBAL-Hで還元し、4(S)-(テトラヒドロ-ピラン-2-イルオキシ)-ペンタ-2-エン-1-オール8（7.6 g）を得た。88%収率。 Part D

4 (S)-(Tetrahydro-pyran-2-yloxy) -pent-2-enoic acid methyl ester 7 (10 g, 46.7 mmol, 1 eq) was synthesized from J. Chem. Soc., Perkin. Trans. 1, 1994, Reduction with DIBAL-H according to the procedure described in 2791 gave 4 (S)-(tetrahydro-pyran-2-yloxy) -pent-2-en-1-ol 8 (7.6 g). 88% yield.

4(S)-(テトラヒドロ-ピラン-2-イルオキシ)-ペンタ-2-エン-1-オール8（4.0 g, 22 mmol, 1 eq）のTHF 20 mL溶液に、イミダゾール（3.66 g, 53.5 mmol, 2.4 eq）、次いでTBSCl（3.89 g, 25.8 mmol, 1.2 eq）を加えた。反応混合物を室温にて4時間撹拌し、水20 mLで反応停止処理し、エーテル（3×10 mL）で抽出した。集めた有機抽出物を水（5×50 mL）、食塩水50 mLで洗浄し、MgSO₄で乾燥し、ろ過し、減圧濃縮した。油状物をシリカゲルクロマトグラフィー（30%ヘキサン/EtOAc）により精製し、9を油状物として5.9 g得た。92%収率。 Part E

To a solution of 4 (S)-(tetrahydro-pyran-2-yloxy) -pent-2-en-1-ol 8 (4.0 g, 22 mmol, 1 eq) in THF 20 mL was added imidazole (3.66 g, 53.5 mmol, 2.4 eq) followed by TBSCl (3.89 g, 25.8 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for 4 hours, quenched with 20 mL of water and extracted with ether (3 × 10 mL). The collected organic extracts were washed with water (5 × 50 mL), brine 50 mL, dried over MgSO ₄ , filtered and concentrated in vacuo. The oil was purified by silica gel chromatography (30% hexane / EtOAc) to give 5.9 g of 9 as an oil. 92% yield.

THP保護基をTetrahedron Letters 1984, 25, 663に記載の手順に従い、t-ブチル-ジメチル-[4(S)-(テトラヒドロ-ピラン-2-イルオキシ)-ペンタ-2-エニルオキシ]-シラン9（10 g, 33 mmol, 1 eq）から除去し、10を油状物として5.9 g得た。83%収率。 Part F

The THP protecting group was t-butyl-dimethyl- [4 (S)-(tetrahydro-pyran-2-yloxy) -pent-2-enyloxy] -silane 9 (10 according to the procedure described in Tetrahedron Letters 1984, 25, 663. g, 33 mmol, 1 eq) to give 5.9 g of 10 as an oil. 83% yield.

ニトロンメチルエステル4（8.1 g, 38 mmol, 1 eq）およびアルコール10（12 g, 38 mmol, 1 eq）のトルエン40 mL溶液に、Ti(OCH(CH₃)₂)₄（16 g, 17 mL, 56 mmol, 1.5 eq）を加えた。懸濁液を140℃まで30分間マイクロウェーブオーブン中にて加熱し、室温まで冷却させた。溶液をEtOAc（150 mL）および3-(ジメチルアミノ)-1,2-プロパンジオール（7 g, 7 mL, 58 mmol, 1.5 eq）で希釈し、室温にて8時間撹拌した。溶液に水100 mLを加え、有機相を分離し、水層をEtOAc（3×30 mL）で洗浄した。集めた有機抽出物を水100 mL、食塩水100 mLで洗浄し、Na₂SO₄で乾燥し、ろ過し、減圧濃縮した。粗製物をシリカゲルクロマトグラフィー（1:29 Et₂O/DCM）により精製し、11を固体として13.5 g得た。71%収率。 Part G

To a 40 mL toluene solution of nitrone methyl ester 4 (8.1 g, 38 mmol, 1 eq) and alcohol 10 (12 g, 38 mmol, 1 eq), Ti (OCH (CH ₃ ) ₂ ) ₄ (16 g, 17 mL , 56 mmol, 1.5 eq). The suspension was heated to 140 ° C. for 30 minutes in a microwave oven and allowed to cool to room temperature. The solution was diluted with EtOAc (150 mL) and 3- (dimethylamino) -1,2-propanediol (7 g, 7 mL, 58 mmol, 1.5 eq) and stirred at room temperature for 8 hours. 100 mL of water was added to the solution, the organic phase was separated, and the aqueous layer was washed with EtOAc (3 × 30 mL). The collected organic extract was washed with 100 mL of water and 100 mL of brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (1:29 Et ₂ O / DCM) to give 13.5 g of 11 as a solid. 71% yield.

To a 120 mL THF solution of TBS protected isoxazolidine (13.5 g, 26 mmol, 1 eq) was added 67 mL 6 N HCl. The solution was stirred at room temperature for 1.5 hours, diluted with 25 mL of water, extracted with EtOAc (3 × 80 mL), the organic extracts collected, washed with saturated NaHCO ₃ (50 mL), brine 50 mL, It was dried over Na ₂ SO ₄ and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (20-33% DCM / ether) to give 9.5 g of 9 as a yellow solid. Total yield of 2 steps 64%.

(+) イソピノカンフェイルアミン12（0.2 g, 1.3 mmol, 6.5 eq）のDCM 10 mL溶液にAlMe₃（トルエン中2 M溶液0.85 mL, 1.7 mmol, 8.5 eq）を2.5分にわたり滴加した。溶液を室温にて10分間撹拌した後、ラクトン11（0.5 g, 0.02 mmol, 1 eq）のDCM 10 mL溶液を滴加した。反応物を1時間撹拌し、DCM 125 mLおよびRochelle塩の飽和水溶液125 mLで希釈した。二相が形成されるまで、混合物を2時間激しく撹拌した。有機相を分離し、水、食塩水で洗浄し、MgSO₄で乾燥し、ろ過し、減圧濃縮して固体を得た。この物質をさらに精製せずに用いた。 Part H

AlMe ₃ (0.85 mL of 2 M solution in toluene, 1.7 mmol, 8.5 eq) was added dropwise over 2.5 minutes to a DCM 10 mL solution of (+) isopinocamphylamine 12 (0.2 g, 1.3 mmol, 6.5 eq). The solution was stirred at room temperature for 10 minutes and then a 10 mL DCM solution of lactone 11 (0.5 g, 0.02 mmol, 1 eq) was added dropwise. The reaction was stirred for 1 hour and diluted with 125 mL DCM and 125 mL saturated aqueous Rochelle salt. The mixture was stirred vigorously for 2 hours until two phases were formed. The organic phase was separated, washed with water, brine, dried over MgSO ₄ , filtered and concentrated in vacuo to give a solid. This material was used without further purification.

ヨウ化アリール13（1.44 g, 2.65 mmol, 1 eq）、ビニルボロン酸14（1.57 g, 10.6 mmol, 10.0 eq）、Na₂CO₃（1.12 g, 10.6 mmol, 10.0 eq）およびパラジウムテトラキス（0.61 g, 0.53 mmol, 0.2 eq）を100 mlフラスコに量りとった。次いでフラスコをアルゴンでパージし、内容物を4:1比のトルエン／水30 mLに溶解し、65℃にて3時間加熱した。有機層を分離し、水層をEtOAc（3×20 mL）で抽出した。有機層を集め、食塩水で洗浄し、MgSO₄で乾燥し、減圧濃縮した。粗製物をシリカゲルクロマトグラフィー（溶媒系）により精製し、15（1.17 g）を得た。85%収率。 Part I

Aryl iodide 13 (1.44 g, 2.65 mmol, 1 eq), vinyl boronic acid 14 (1.57 g, 10.6 mmol, 10.0 eq), Na ₂ CO ₃ (1.12 g, 10.6 mmol, 10.0 eq) and palladium tetrakis (0.61 g, 0.53 mmol, 0.2 eq) was weighed into a 100 ml flask. The flask was then purged with argon and the contents were dissolved in 30 mL of a 4: 1 ratio of toluene / water and heated at 65 ° C. for 3 hours. The organic layer was separated and the aqueous layer was extracted with EtOAc (3 × 20 mL). The organic layer was collected, washed with brine, dried over MgSO ₄ and concentrated in vacuo. The crude product was purified by silica gel chromatography (solvent system) to give 15 (1.17 g). 85% yield.

15（0.11 g, 0.21 mmol, 1 eq）のtBuOH 16 ml溶液、THF 8 ml、水2 mlの溶液に、NMO（0.11 g, 0.82 mmol, 4 eq）およびOsO₄（2 mL, 0.21 g, 0.021 mmol, 1 eq）の2.5 % tBuOH溶液を加えた。4時間撹拌後、Na₂S₂O₃の溶液で反応停止処理し、EtOAc／食塩水で分液した。水層を洗浄し、MgSO₄で有機物を乾燥し、ろ過し、減圧濃縮し、油状物を得た。
次いで粗製物（10 mg, 18μmol, 1 eq）をTHF 0.2 mLに取り、これに水20μLおよび過ヨウ素酸ナトリウム（4.1 mg, 19μmol, 1.05 eq）を加え、反応混合物を終夜撹拌した。Na₂S₂O₃で反応停止処理し、食塩水で洗浄し、MgSO₄で乾燥し、減圧濃縮した。粗製物をシリカゲルクロマトグラフィーにより精製し、16（6.8 mg）を灰白色固体として得た。85%収率。 Part J

To a solution of 15 (0.11 g, 0.21 mmol, 1 eq) in tBuOH 16 ml, THF 8 ml, water 2 ml, NMO (0.11 g, 0.82 mmol, 4 eq) and OsO ₄ (2 mL, 0.21 g, 0.021 mmol, 1 eq) in 2.5% tBuOH. After stirring for 4 hours, the reaction was quenched with a solution of Na ₂ S ₂ O ₃ and partitioned between EtOAc / brine. The aqueous layer was washed and the organics were dried over MgSO ₄ , filtered and concentrated under reduced pressure to give an oil.
The crude product (10 mg, 18 μmol, 1 eq) was then taken up in 0.2 mL of THF, to which 20 μL of water and sodium periodate (4.1 mg, 19 μmol, 1.05 eq) were added and the reaction mixture was stirred overnight. The reaction was quenched with Na ₂ S ₂ O ₃ , washed with brine, dried over MgSO ₄ and concentrated in vacuo. The crude product was purified by silica gel chromatography to give 16 (6.8 mg) as an off-white solid. 85% yield.

アルデヒド16（40 mg, 90μmol, 1 eq）の1%水性MeOH 2 mL溶液をアミン17（41μL, 0.23 mmol, 2.6 eq.）で処理し、1時間撹拌した。NaBH4（4 mg, 90μmol, 1 eq.）を加え、混合物を0.5時間撹拌し、AcOH 10μLで反応停止処理した。 Part K

A solution of aldehyde 16 (40 mg, 90 μmol, 1 eq) in 1% aqueous MeOH was treated with amine 17 (41 μL, 0.23 mmol, 2.6 eq.) And stirred for 1 hour. NaBH4 (4 mg, 90 μmol, 1 eq.) Was added and the mixture was stirred for 0.5 h and quenched with 10 μL AcOH.

Half of this crude reaction mixture was treated with 2,3-methylenedioxybenzaldehyde 18 (34 mg, 0.23 mmol, 5 eq.); After 0.25 h, NaBH ₃ CN (12 mg, 0.23 mmol, 5 eq.) Was In addition, stirring was continued overnight. The reaction mixture was directly purified by reverse phase HPLC (CH ₃ CN / 40 mM NH ₄ HCO ₃ in water) to give 1 (20 mg) as a white solid. 63% yield. MS (ESI (+)) m / z 707.76 (M + H) ⁺ .

2,3-メチレンジオキシベンズアルデヒドの代わりに3-エトキシサリチルアルデヒドを用いて、化合物19を実施例1記載の手順に従い合成した。34%収率。MS (ESI(+)) m/z 723.82 (M+H)⁺. Example 2

Compound 19 was synthesized according to the procedure described in Example 1 using 3-ethoxysalicylaldehyde in place of 2,3-methylenedioxybenzaldehyde. 34% yield. MS (ESI (+)) m / z 723.82 (M + H) ⁺ .

2,3-メチレンジオキシベンズアルデヒドの代わりに6-メトキシサリチルアルデヒドを用いて、化合物20を実施例1記載の手順に従い合成した。29%収率。MS (ESI(+)) m/z 709.79 (M+H)⁺. Example 3

Compound 20 was synthesized according to the procedure described in Example 1 using 6-methoxysalicylaldehyde instead of 2,3-methylenedioxybenzaldehyde. 29% yield. MS (ESI (+)) m / z 709.79 (M + H) ⁺ .

2,3-メチレンジオキシベンズアルデヒドの代わりに6-フルオロサリチルアルデヒドを用いて、化合物21を実施例1記載の手順に従い合成した。38%収率。MS (ESI(+)) m/z 711.83 (M+H)⁺. Example 4

Compound 21 was synthesized according to the procedure described in Example 1 using 6-fluorosalicylaldehyde instead of 2,3-methylenedioxybenzaldehyde. 38% yield. MS (ESI (+)) m / z 711.83 (M + H) ⁺ .

2,3-メチレンジオキシベンズアルデヒドの代わりに2-クロロベンズアルデヒドを用いて、化合物22を実施例1記載の手順に従い合成した。35%収率。
MS (ESI(+)) m/z 740.68 (M+H)⁺. Example 5

Compound 22 was synthesized according to the procedure described in Example 1 using 2-chlorobenzaldehyde instead of 2,3-methylenedioxybenzaldehyde. 35% yield.
MS (ESI (+)) m / z 740.68 (M + H) ⁺ .

2,3-メチレンジオキシベンズアルデヒドの代わりに2-アリルオキシベンズアルデヒドを用いて、化合物23を実施例1記載の手順に従い合成した。50%収率。MS (ESI(+)) m/z 719.82 (M+H)⁺. Example 6

Compound 23 was synthesized according to the procedure described in Example 1 using 2-allyloxybenzaldehyde instead of 2,3-methylenedioxybenzaldehyde. 50% yield. MS (ESI (+)) m / z 719.82 (M + H) ⁺ .

2,3-メチレンジオキシベンズアルデヒドの代わりに2-エトキシベンズアルデヒドを用いて、化合物24を実施例1記載の手順に従い合成した。25%収率。MS (ESI(+)) m/z 707.82 (M+H)⁺. Example 7

Compound 24 was synthesized according to the procedure described in Example 1 using 2-ethoxybenzaldehyde instead of 2,3-methylenedioxybenzaldehyde. 25% yield. MS (ESI (+)) m / z 707.82 (M + H) ⁺ .

2,3-メチレンジオキシベンズアルデヒドの代わりに2-(メチルチオ)ベンズアルデヒドを用いて、化合物25を実施例1記載の手順に従い合成した。38%収率。MS (ESI(+)) m/z 709.72 (M+H)⁺. Example 8

Compound 25 was synthesized according to the procedure described in Example 1 using 2- (methylthio) benzaldehyde instead of 2,3-methylenedioxybenzaldehyde. 38% yield. MS (ESI (+)) m / z 709.72 (M + H) ⁺ .

2,3-メチレンジオキシベンズアルデヒドの代わりに4-ホルミルインドールを用いて、化合物26を実施例1記載の手順に従い合成した。25%収率。MS (ESI(+)) m/z 702.80 (M+H)⁺. Example 9

Compound 26 was synthesized according to the procedure described in Example 1 using 4-formylindole instead of 2,3-methylenedioxybenzaldehyde. 25% yield. MS (ESI (+)) m / z 702.80 (M + H) ⁺ .

2,3-メチレンジオキシベンズアルデヒドの代わりに3-ヒドロキシベンズアルデヒドを、アミン17の代わりに(S)-N¹,N¹-ジメチル-2-フェニルエタン-1,2-ジアミンを用いて、化合物27を実施例1記載の手順に従い合成した。45%収率。MS (ESI(+)) m/z 666.89 (M+H)⁺. Example 10

Compound 27 using 3-hydroxybenzaldehyde in place of 2,3-methylenedioxybenzaldehyde and (S) -N ¹ , N ¹ -dimethyl-2-phenylethane-1,2-diamine in place of amine 17 Was synthesized according to the procedure described in Example 1. 45% yield. MS (ESI (+)) m / z 666.89 (M + H) ⁺ .

2,3-メチレンジオキシベンズアルデヒドの代わりに3-ヒドロキシベンズアルデヒドを、アミン17の代わりに(S)-N¹,N¹,3-トリメチルブタン-1,2-ジアミンを用いて、化合物28を実施例1記載の手順に従い合成した。47%収率。MS (ESI(+)) m/z 665.85 (M+H)⁺. Example 11

Compound 28 was performed using 3-hydroxybenzaldehyde in place of 2,3-methylenedioxybenzaldehyde and (S) -N ¹ , N ¹ , 3-trimethylbutane-1,2-diamine in place of amine 17 Synthesized according to the procedure described in Example 1. 47% yield. MS (ESI (+)) m / z 665.85 (M + H) ⁺ .

2,3-メチレンジオキシベンズアルデヒドの代わりにシクロペンタンカルボキシアルデヒドを、アミン17の代わりに(S)-N¹,N¹,4,4-テトラメチルペンタン-1,2-ジアミンを用いて、化合物29を実施例1記載の手順に従い合成した。37%収率。MS (ESI(+)) m/z 669.91 (M+H)⁺. Example 12

Compound using cyclopentanecarboxaldehyde instead of 2,3-methylenedioxybenzaldehyde and (S) -N ¹ , N ¹ , 4,4-tetramethylpentane-1,2-diamine instead of amine 17 29 was synthesized according to the procedure described in Example 1. 37% yield. MS (ESI (+)) m / z 669.91 (M + H) ⁺ .

2,3-メチレンジオキシベンズアルデヒドの代わりに3-ヒドロキシベンズアルデヒドを、アミン17の代わりにアミン (S)-N¹,N¹,4,4-テトラメチルペンタン-1,2-ジアミンを用いて、化合物30を実施例1記載の手順に従い合成した。48%収率。MS (ESI(+)) m/z 693.92 (M+H)⁺. Example 13

Using 3-hydroxybenzaldehyde in place of 2,3-methylenedioxybenzaldehyde and amine (S) -N ¹ , N ¹ , 4,4-tetramethylpentane-1,2-diamine in place of amine 17 Compound 30 was synthesized according to the procedure described in Example 1. 48% yield. MS (ESI (+)) m / z 693.92 (M + H) ⁺ .

2,3-メチレンジオキシベンズアルデヒドの代わりに2-クロロ-6-フルオロベンズアルデヒドを、アミン17の代わりに(S)-N¹,N¹,4,4-テトラメチルペンタン-1,2-ジアミンを用いて、化合物31を実施例1記載の手順に従い合成した。52%収率。MS (ESI(+)) m/z 729.86 (M+H)⁺. Example 14

2-chloro-6-fluorobenzaldehyde instead of 2,3-methylenedioxybenzaldehyde, (S) -N ¹ , N ¹ , 4,4-tetramethylpentane-1,2-diamine instead of amine 17 Using, compound 31 was synthesized according to the procedure described in Example 1. 52% yield. MS (ESI (+)) m / z 729.86 (M + H) ⁺ .

2,3-メチレンジオキシベンズアルデヒドの代わりに2-クロロ-6-フルオロベンズアルデヒドを、アミン17の代わりに(S)-N¹,N¹,3-トリメチルブタン-1,2-ジアミンを用いて、化合物32を実施例1記載の手順に従い合成した。35%収率。MS (ESI(+)) m/z 701.79 (M+H)⁺. Example 15

Using 2-chloro-6-fluorobenzaldehyde in place of 2,3-methylenedioxybenzaldehyde and (S) -N ¹ , N ¹ , 3-trimethylbutane-1,2-diamine in place of amine 17, Compound 32 was synthesized according to the procedure described in Example 1. 35% yield. MS (ESI (+)) m / z 701.79 (M + H) ⁺ .

2,3-メチレンジオキシベンズアルデヒドの代わりに2-クロロ-6-フルオロベンズアルデヒドを、アミン17の代わりに(S)-N¹,N¹-ジメチル-2-フェニルエタン-1,2-ジアミンを用いて、化合物44を実施例1記載の手順に従い合成した。21%収率。MS (ESI(+)) m/z 735.83 (M+H)⁺. Example 16

Use 2-chloro-6-fluorobenzaldehyde in place of 2,3-methylenedioxybenzaldehyde and (S) -N ¹ , N ¹ -dimethyl-2-phenylethane-1,2-diamine in place of amine 17 Compound 44 was synthesized according to the procedure described in Example 1. 21% yield. MS (ESI (+)) m / z 735.83 (M + H) ⁺ .

2,3-メチレンジオキシベンズアルデヒドの代わりに2-クロロベンズアルデヒドを、アミン17の代わりに(S)-N¹,N¹-ジメチルペンタン-1,2-ジアミンを用いて、化合物34を実施例1記載の手順に従い合成した。53%収率。MS (ESI(+)) m/z 683.75 (M+H)⁺. Example 17

Compound 34 was prepared in Example 1 using 2-chlorobenzaldehyde in place of 2,3-methylenedioxybenzaldehyde and (S) -N ¹ , N ¹ -dimethylpentane-1,2-diamine in place of amine 17. Synthesized according to the described procedure. 53% yield. MS (ESI (+)) m / z 683.75 (M + H) ⁺ .

2,3-メチレンジオキシベンズアルデヒドの代わりに2-クロロ-6-フルオロベンズアルデヒドを用い、アミン17の代わりに(S)-1-(1-ピロリジニル)-2-アミノ-4-メチル-ペンタンを用いて、化合物35を実施例1記載の手順に従い合成した。30%収率。MS (ESI(+)) m/z 741.86 (M+H)⁺. Example 18

2-Chloro-6-fluorobenzaldehyde is used in place of 2,3-methylenedioxybenzaldehyde, and (S) -1- (1-pyrrolidinyl) -2-amino-4-methyl-pentane is used in place of amine 17. Compound 35 was synthesized according to the procedure described in Example 1. 30% yield. MS (ESI (+)) m / z 741.86 (M + H) ⁺ .

2,3-メチレンジオキシベンズアルデヒドの代わりに2-トリフルオロメチル-6-フルオロベンズアルデヒドを、アミン17の代わりに(S)-1-(1-ピロリジニル)-2-アミノ-4-メチル-ペンタンを用いて、化合物36を実施例1記載の手順に従い合成した。23%収率。MS (ESI(+)) m/z 775.90 (M+H)⁺. Example 19

2-trifluoromethyl-6-fluorobenzaldehyde in place of 2,3-methylenedioxybenzaldehyde, (S) -1- (1-pyrrolidinyl) -2-amino-4-methyl-pentane in place of amine 17 Compound 36 was used according to the procedure described in Example 1. 23% yield. MS (ESI (+)) m / z 775.90 (M + H) ⁺ .

2,3-メチレンジオキシベンズアルデヒドの代わりに6-フルオロサリチルアルデヒドを、アミン17の代わりに(S)-1-(1-ピロリジニル)-2-アミノ-4-メチル-ペンタンを用いて、化合物37を実施例1記載の手順に従い合成した。31%収率。MS (ESI(+)) m/z 723.89 (M+H)⁺. Example 20

Using 6-fluorosalicylaldehyde in place of 2,3-methylenedioxybenzaldehyde and (S) -1- (1-pyrrolidinyl) -2-amino-4-methyl-pentane in place of amine 17, compound 37 Was synthesized according to the procedure described in Example 1. 31% yield. MS (ESI (+)) m / z 723.89 (M + H) ⁺ .

パートA

ケトン39（500 mg, 2.42 mmol, 1 eq）のDCE 5 mL溶液にN¹,N¹-ジメチルエタン-1,2-ジアミン（641 mg, 7.27 mmol, 3 eq）、次いでNa(OAc)₃BH（771 mg, 3.64 mmol, 1.5 eq）を加え、反応物を40℃まで加熱した。48時間撹拌した後、反応混合物を水100 mL、EtOAc 100 mL、食塩水100 mLで希釈し、pHを6 N NaOHで12に調節した。混合物をEtOAc（2×100 mL）で抽出し、集めた有機物をMgSO₄で乾燥し、ろ過し、減圧濃縮してジアミン40（200 mg）を暗茶色油状物として得た。粗製の油状物をさらに精製せずに直接用いた。 Example 21

Part A

N ¹ , N ¹ -Dimethylethane-1,2-diamine (641 mg, 7.27 mmol, 3 eq) in a solution of ketone 39 (500 mg, 2.42 mmol, 1 eq) in 5 mL of DCE, then Na (OAc) ₃ BH (771 mg, 3.64 mmol, 1.5 eq) was added and the reaction was heated to 40 ° C. After stirring for 48 hours, the reaction mixture was diluted with 100 mL water, 100 mL EtOAc, 100 mL brine and the pH was adjusted to 12 with 6 N NaOH. The mixture was extracted with EtOAc (2 × 100 mL) and the collected organics were dried over MgSO ₄ , filtered and concentrated in vacuo to give diamine 40 (200 mg) as a dark brown oil. The crude oil was used directly without further purification.

アルデヒド16（30 mg, 0.07 mmol）のDCE 1 mL溶液に、ジアミン40（0.02 mg, 0.07 mmol）、次いでNa(OAc)₃BH（20 mg, 0.1 mmol）を加え、反応物を40℃まで加熱した。48時間撹拌した後、アルデヒドの別の一部（30 mg, 0.02 mmol）およびNa(OAc)₃BH（20 mg, 0.1 mmol）を加え、反応物を40℃にて撹拌した。24時間後、反応混合物を逆相HPLC（CH₃CN／40 mM NH₄HCO₃を含む水）により直接精製し、38（20 mg）を得た。収率42%。MS (ESI(+)) m/z 707.5. (M+H)⁺. Part B

To a 1 mL solution of aldehyde 16 (30 mg, 0.07 mmol) in DCE is added diamine 40 (0.02 mg, 0.07 mmol), then Na (OAc) ₃ BH (20 mg, 0.1 mmol), and the reaction is heated to 40 ° C. did. After stirring for 48 hours, another portion of aldehyde (30 mg, 0.02 mmol) and Na (OAc) ₃ BH (20 mg, 0.1 mmol) were added and the reaction was stirred at 40 ° C. After 24 hours, the reaction mixture was directly purified by reverse phase HPLC (CH ₃ CN / 40 mM NH ₄ HCO ₃ in water) to give 38 (20 mg). Yield 42%. MS (ESI (+)) m / z 707.5. (M + H) ⁺ .

2,3-メチレンジオキシベンズアルデヒドの代わりに2-ブロモ-5-(ヒドロキシル)ベンズアルデヒドを用いて、化合物41を実施例1記載の手順に従い合成した。収率38%。MS (ESI(+)) m/z 757.6 (M+H)⁺. Example 22

Compound 41 was synthesized according to the procedure described in Example 1 using 2-bromo-5- (hydroxyl) benzaldehyde instead of 2,3-methylenedioxybenzaldehyde. Yield 38%. MS (ESI (+)) m / z 757.6 (M + H) ⁺ .

2,3 メチレンジオキシベンズアルデヒドの代わりに2-ホルミルチオフェン-2-カルボン酸を用いて、化合物42を実施例1記載の手順に従い合成した。収率48%。MS (ESI(+)) m/z 713.8 (M+H)⁺. Example 23

Compound 42 was synthesized according to the procedure described in Example 1 using 2-formylthiophene-2-carboxylic acid instead of 2,3 methylenedioxybenzaldehyde. Yield 48%. MS (ESI (+)) m / z 713.8 (M + H) ⁺ .

2,3 メチレンジオキシベンズアルデヒドの代わりに2,4-ジクロロ-6-ヒドロキシルベンズアルデヒドを用いて、化合物43を実施例1記載の手順に従い合成した。収率27%。MS (ESI(+)) m/z 747.8 (M+H)⁺. Example 24

Compound 43 was synthesized according to the procedure described in Example 1 using 2,4-dichloro-6-hydroxylbenzaldehyde instead of 2,3 methylenedioxybenzaldehyde. Yield 27%. MS (ESI (+)) m / z 747.8 (M + H) ⁺ .

2,3 メチレンジオキシベンズアルデヒドの代わりに2-ホルミルフェノキシ酢酸を用いて、化合物44を実施例1記載の手順に従い合成した。収率47%. MS (ESI(+)) m/z 737.7 (M+H)⁺. Example 25

Compound 44 was synthesized according to the procedure described in Example 1 using 2-formylphenoxyacetic acid instead of 2,3 methylenedioxybenzaldehyde. Yield 47%. MS (ESI (+)) m / z 737.7 (M + H) ⁺ .

2,3 メチレンジオキシベンズアルデヒドの代わりにチオフェン-2-カルボキシアルデヒドを用いて、化合物45を実施例1記載の手順に従い合成した。収率69%. MS (ESI(+)) m/z 669.8 (M+H)⁺. Example 26

Compound 45 was synthesized according to the procedure described in Example 1 using thiophene-2-carboxaldehyde instead of 2,3 methylenedioxybenzaldehyde. Yield 69%. MS (ESI (+)) m / z 669.8 (M + H) ⁺ .

2,3 メチレンジオキシベンズアルデヒドの代わりにo-トルアルデヒドを用いて、化合物46を実施例1記載の手順に従い合成した。収率51%. MS (ESI(+)) m/z 677.9 (M+H)⁺. Example 27

Compound 46 was synthesized according to the procedure described in Example 1 using o-tolualdehyde instead of 2,3 methylenedioxybenzaldehyde. Yield 51%. MS (ESI (+)) m / z 677.9 (M + H) ⁺ .

2,3 メチレンジオキシベンズアルデヒドの代わりに1-メチルピロール-2-カルボキシアルデヒドを用いて、化合物47を実施例1記載の手順に従い合成した。収率43%. MS (ESI(+)) m/z 666.9 (M+H)⁺. Example 28

Compound 47 was synthesized according to the procedure described in Example 1 using 1-methylpyrrole-2-carboxaldehyde instead of 2,3 methylenedioxybenzaldehyde. Yield 43%. MS (ESI (+)) m / z 666.9 (M + H) ⁺ .

2,3 メチレンジオキシベンズアルデヒドの代わりに2-カルボキシベンズアルデヒドを用いて、化合物48を実施例1記載の手順に従い合成した。収率65%. MS (ESI(+)) m/z 707.9 (M+H)⁺. Example 29

Compound 48 was synthesized according to the procedure described in Example 1 using 2-carboxybenzaldehyde instead of 2,3 methylenedioxybenzaldehyde. Yield 65%. MS (ESI (+)) m / z 707.9 (M + H) ⁺ .

2,3-メチレンジオキシベンズアルデヒドの代わりにチオフェン-3-カルボキシアルデヒドを用いて、化合物49を実施例1記載の手順に従い合成した。収率69%. MS (ESI(+)) m/z 669.8 (M+H)⁺. Example 30

Compound 49 was synthesized according to the procedure described in Example 1 using thiophene-3-carboxaldehyde instead of 2,3-methylenedioxybenzaldehyde. Yield 69%. MS (ESI (+)) m / z 669.8 (M + H) ⁺ .

2,3 メチレンジオキシベンズアルデヒドの代わりに4-フルオロ-2-ヒドロキシベンズアルデヒドを用いて、化合物50を実施例1記載の手順に従い合成した。収率15%. MS (ESI(+)) m/z 697.8 (M+H)⁺. Example 31

Compound 50 was synthesized according to the procedure described in Example 1 using 4-fluoro-2-hydroxybenzaldehyde instead of 2,3 methylenedioxybenzaldehyde. Yield 15%. MS (ESI (+)) m / z 697.8 (M + H) ⁺ .

パートA

Boc-L-ロイシン53（5 g, 22 mmol, 1 eq）およびPyBop（15 g, 28 mmol, 1.3）のDCM 60 mL溶液に、ピロリジンを0℃にて加えた。溶液を10分間撹拌した後、DIPEA（6 g, 8 mL, 48 mmol, 2.2 eq）を滴加した。6時間撹拌した後、溶液を飽和NaHCO₃（40 mL）で希釈し、水相をDCM（2×50 mL）で抽出した。集めた有機相を食塩水で洗浄し、分離し、MgSO₄で乾燥し、ろ過し、減圧濃縮し、油状物を得た。得られた油状物をシリカゲルクロマトグラフィー（50-100%ヘキサン/EtOAc）により精製し、53を透明油状物として得た。 Example 32

Part A

Pyrrolidine was added to a solution of Boc-L-leucine 53 (5 g, 22 mmol, 1 eq) and PyBop (15 g, 28 mmol, 1.3) in DCM (60 mL) at 0 ° C. The solution was stirred for 10 minutes before DIPEA (6 g, 8 mL, 48 mmol, 2.2 eq) was added dropwise. After stirring for 6 hours, the solution was diluted with saturated NaHCO ₃ (40 mL) and the aqueous phase was extracted with DCM (2 × 50 mL). The collected organic phases were washed with brine, separated, dried over MgSO ₄ , filtered and concentrated in vacuo to give an oil. The resulting oil was purified by silica gel chromatography (50-100% hexane / EtOAc) to give 53 as a clear oil.

アミド53（4.5 g, 15.8 mmol, 1 eq）のDCM 100 mL溶液に、TFA 10 mLを0℃にて加えた。2時間室温にて撹拌した後、溶媒を減圧留去し、油状物を得た。得られた油状物をTHFに懸濁させ、0℃まで冷却し、これにLiAlH₄（4 g, 108 mmol, 6.8 eq）を少しずつ加え、アルゴン雰囲気下、還流温度にて12時間加熱した。溶液を室温まで冷却し、水4 mLで反応停止処理し、5分間撹拌し、次いで15% NaOH 4 mLを加えてさらに5分間撹拌し、最後に水12 mLを加え、白色析出物が形成されるまで懸濁物を撹拌した。固体をろ過し、EtOAcで洗浄し、ろ液を減圧濃縮し、54を油状物として得、これをさらに精製せずに用いた。 Part B

To a 100 mL DCM solution of amide 53 (4.5 g, 15.8 mmol, 1 eq), 10 mL TFA was added at 0 ° C. After stirring at room temperature for 2 hours, the solvent was distilled off under reduced pressure to obtain an oil. The obtained oil was suspended in THF, cooled to 0 ° C., LiAlH ₄ (4 g, 108 mmol, 6.8 eq) was added little by little, and the mixture was heated at reflux temperature for 12 hours under an argon atmosphere. Cool the solution to room temperature, quench with 4 mL of water, stir for 5 minutes, then add 4 mL of 15% NaOH and stir for an additional 5 minutes, and finally add 12 mL of water to form a white precipitate. The suspension was stirred until The solid was filtered and washed with EtOAc and the filtrate was concentrated in vacuo to give 54 as an oil that was used without further purification.

16（250 mg, 0.56 mmol, 1 eq）のMeOH 25 mL溶液に、54（96 mg, 0.56 mmol, 1 eq）を加え、室温にて3時間撹拌し、次いでNaBH₄（21 mg, 0.56 mmol, 1 eq）を加えた。室温にて12時間撹拌した後、反応混合物をAcOH 0.08 mLで希釈し、減圧濃縮し、油状物を得、これをさらに精製せずに用いた。 Part C

To a solution of 16 (250 mg, 0.56 mmol, 1 eq) in MeOH in 25 mL, 54 (96 mg, 0.56 mmol, 1 eq) was added and stirred at room temperature for 3 hours, then NaBH ₄ (21 mg, 0.56 mmol, 1 eq) was added. After stirring at room temperature for 12 hours, the reaction mixture was diluted with AcOH 0.08 mL and concentrated under reduced pressure to give an oil that was used without further purification.

55（15 mg, 25μmol, 1 eq）のDCM 1.0 mL溶液に、2-ヒドロキシベンズアルデヒド（5 mg, 38μmol, 1.5 eq）、次いでNa(OAc)₃BH（11 mg, 50μmol, 2 eq）を加えた。室温にて12時間撹拌した後、反応混合物をAcOH 0.1 mLで希釈し、10分間撹拌した。反応混合物をDCM 2.5 mLで希釈し、飽和NaHCO₃ 2.5 mLで洗浄し、有機相を分離し、Na₂SO₄で乾燥し、減圧濃縮し、油状物を得た。油状物を逆相HPLC（CH₃CN／40 mM NH₄HCO₃を含む水）により直接精製し、51（7 mg）を白色固体として得た。収率 40%. MS (ESI(+)) m/z 705.9 (M+H)⁺. Part D

To a 1.0 mL DCM solution of 55 (15 mg, 25 μmol, 1 eq), 2-hydroxybenzaldehyde (5 mg, 38 μmol, 1.5 eq) was added, followed by Na (OAc) ₃ BH (11 mg, 50 μmol, 2 eq) . After stirring at room temperature for 12 hours, the reaction mixture was diluted with AcOH 0.1 mL and stirred for 10 minutes. The reaction mixture was diluted with 2.5 mL DCM, washed with 2.5 mL saturated NaHCO ₃ , the organic phase was separated, dried over Na ₂ SO ₄ and concentrated in vacuo to give an oil. The oil was directly purified by reverse phase HPLC (CH ₃ CN / 40 mM NH ₄ HCO ₃ in water) to give 51 (7 mg) as a white solid. Yield 40%. MS (ESI (+)) m / z 705.9 (M + H) ⁺ .

2-ヒドロキシベンズアルデヒドの代わりに2-ホルミルベンゼンスルホン酸を用いて、化合物57を実施例32記載の手順に従い合成した。収率39%. MS (ESI(+)) m/z 705.9 (M+H)⁺. Example 33

Compound 57 was synthesized according to the procedure described in Example 32 using 2-formylbenzenesulfonic acid instead of 2-hydroxybenzaldehyde. Yield 39%. MS (ESI (+)) m / z 705.9 (M + H) ⁺ .

2-ヒドロキシベンズアルデヒドの代わりに2-(2-ヒドロキシエトキシ)ベンズアルデヒドを用いて、化合物58を実施例32記載の手順に従い合成した。収率32%. MS (ESI(+)) m/z 749.9 (M+H)⁺. Example 34

Compound 58 was synthesized according to the procedure described in Example 32 using 2- (2-hydroxyethoxy) benzaldehyde in place of 2-hydroxybenzaldehyde. Yield 32%. MS (ESI (+)) m / z 749.9 (M + H) ⁺ .

2-ヒドロキシベンズアルデヒドの代わりに5-ブロモチオフェン-2-カルボキシアルデヒドを用いて、化合物59を実施例32記載の手順に従い合成した。収率54%. MS (ESI(+)) m/z 775.7 (M+H)⁺. Example 35

Compound 59 was synthesized according to the procedure described in Example 32 using 5-bromothiophene-2-carboxaldehyde instead of 2-hydroxybenzaldehyde. Yield 54%. MS (ESI (+)) m / z 775.7 (M + H) ⁺ .

2-ヒドロキシベンズアルデヒドの代わりに2-(2-ホルミル-フェノキシ)-アセトアミドを用いて、化合物60を実施例32記載の手順に従い合成した。収率35%. MS (ESI(+)) m/z 762.9 (M+H)⁺. Example 36

Compound 60 was synthesized according to the procedure described in Example 32 using 2- (2-formyl-phenoxy) -acetamide instead of 2-hydroxybenzaldehyde. Yield 35%. MS (ESI (+)) m / z 762.9 (M + H) ⁺ .

2-ヒドロキシベンズアルデヒドの代わりに2-ホルミルフェノキシ酢酸を用いて、化合物61を実施例32記載の手順に従い合成した。収率59%. MS (ESI(+)) m/z 775.7 (M+H)⁺. Example 37

Compound 61 was synthesized according to the procedure described in Example 32 using 2-formylphenoxyacetic acid instead of 2-hydroxybenzaldehyde. Yield 59%. MS (ESI (+)) m / z 775.7 (M + H) ⁺ .

61（10 mg, 10μmol, 1 eq）のDMF 0.5 mL溶液に、PyBop（10 mg, 20μmol, 2 eq）、モルホリン（2 mg, 30μmol, 3 eq）およびEt₃N（4 mg, 5 uL, 40μmol, 4 eq）を加えた。溶液を12時間撹拌し、水0.5 mLで希釈し、反応混合物を逆相HPLC（CH3CN／40 mM NH₄HCO₃を含む水）により直接精製し、62（3 mg）を白色固体として得た。収率28%. MS (ESI(+)) m/z 833 (M+H)⁺. Example 38

61 (10 mg, 10 μmol, 1 eq) in DMF 0.5 mL was added to PyBop (10 mg, 20 μmol, 2 eq), morpholine (2 mg, 30 μmol, 3 eq) and Et ₃ N (4 mg, 5 uL, 40 μmol) , 4 eq). The solution was stirred for 12 hours, diluted with 0.5 mL of water and the reaction mixture was directly purified by reverse phase HPLC (CH3CN / 40 mM NH ₄ HCO ₃ in water) to give 62 (3 mg) as a white solid. Yield 28%. MS (ESI (+)) m / z 833 (M + H) ⁺ .

モルホリンの代わりにジメチルアミンを用いて、化合物63を実施例38記載の手順に従い合成した。収率59%. MS (ESI(+)) m/z 775.7 (M+H)⁺. Example 39

Compound 63 was synthesized according to the procedure described in Example 38 using dimethylamine instead of morpholine. Yield 59%. MS (ESI (+)) m / z 775.7 (M + H) ⁺ .

シクロヘキシル(2-フルオロフェニル)メタノンの代わりにシクロヘキシル(フェニル)メタノンを用いて、化合物64を実施例21記載の手順に従い合成した。収率29%. MS (ESI(+)) m/z 689.49 (M+H)⁺. Example 40

Compound 64 was synthesized according to the procedure described in Example 21 using cyclohexyl (phenyl) methanone instead of cyclohexyl (2-fluorophenyl) methanone. Yield 29%. MS (ESI (+)) m / z 689.49 (M + H) ⁺ .

Example 41
Bcl-2 binding affinity data for various compounds of the present invention are shown below. As shown in the table below, “***” indicates that Ki is <1 nM; “***” indicates that Ki is 1-5 nM; “***” indicates that Ki is 5 Indicates −9 nM; and “*” indicates that Ki is> 9 nM.

  Bcl-xL binding affinity data for various compounds of the present invention are shown below. As shown in the table below, “†††” indicates that Ki is <0.2 μM; “††” indicates that Ki is 0.2-1 μM; “†” indicates that Ki is> 1 μM Indicates.

References Reference is made to all US patents and US patent application publications cited herein.

Equivalents Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.

Claims (27)

Formula 1:

[In the formula, each independently,
n is 0, 1, 2, 3 or 4;
Each R ¹ is independently H, alkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl, halide, hydroxyl, alkoxyl, aryloxy, acyloxy, amino, alkylamino, arylamino, acylamino , aralkylamino, nitro, acylthio, carboxamide, carboxyl, _{^{nitrile, -COR 5, -CO 2 R 5}} , -N (R 5) CO 2 R 6, -OC (O) N (R 5) (R 6), It is _{^{-N (R 5) SO 2 R}} 6 or ^{-N (R 5) C (O} ) N (R 5) (R 6);
R ² and R ³ are each independently H, alkyl, alkenyl, alkynyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, heteroaralkyl or — [C (R ⁵ ) (R ⁶ )] _p —R ⁴ Or is Formula 1a:

(Where
m is 0, 1, 2, 3, 4 or 5;
Each R ⁷ is independently H, alkyl, aryl, alkenyl, halide, hydroxyl, alkoxyl, alkenyloxy, aryloxy, acyloxy, amino, alkylamino, arylamino, acylamino, aralkylamino, nitro, acylthio, carboxamide, carboxyl, Nitrile, -OSO ₃ R ⁵ , -SO ₂ R ⁵ , -S (O) R ⁵ , -SR ⁵ , -PO ₂ OR ⁵ , -OPO ₂ OR ⁵ , -COR ⁵ , -CO ₂ R ⁵ , -OCH ₂ CO ₂ R ⁵ or —OCH ₂ C (O) N (R ⁵ ) (R ⁶ ); or two R ⁷ together are monocyclic rings of 5-8 ring atoms (the ring 1, 2 or 3 atoms can be independently S, O or N)
Having a group represented by:
R ⁴ is halide, hydroxyl, alkoxyl, aryloxy, acyloxy, amino, alkylamino, arylamino, acylamino, aralkylamino, nitro, acylthio, carboxamide, carboxyl, nitrile, -OSO ₃ R ⁵ , -SO ₂ R ⁵ ,- S (O) R ⁵ , -PO ₂ OR ⁵ , -OPO ₂ OR ⁵ , -COR ⁵ , -CO ₂ R ⁵ , -N (R ⁵ ) CO ₂ R ⁶ , -OC (O) N (R ⁵ ) (R ⁶ ), —N (R ⁵ ) SO ₂ R ⁶ or —N (R ⁵ ) C (O) N (R ⁵ ) (R ⁶ );
R ⁵ and R ⁶ are each independently H, alkyl, alkenyl, alkynyl, aryl, aralkyl, cycloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroaralkyl; or R ⁵ and R ^{6 taken} together Can form a monocyclic ring of 4-8 ring atoms (1, 2 or 3 atoms of the ring atoms are independently S, O or N)]
Or a pharmaceutically acceptable salt thereof. The following compounds:

A compound selected from the group consisting of:   A pharmaceutical composition comprising a compound according to claim 1 or 2 and at least one pharmaceutically acceptable excipient.   A method for treating cancer, comprising a step of administering a therapeutically effective amount of the compound according to claim 1 or 2 to a patient in need thereof.   Cancer is follicular lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, chronic lymphocytic leukemia prostate cancer, breast cancer, neuroblastoma, colorectal cancer, endometrial cancer, ovarian cancer The method according to claim 4, which is lung cancer, hepatocellular carcinoma, multiple myeloma, head and neck cancer or testicular cancer.   The method of claim 4, wherein the cancer overexpresses Bcl protein.   5. The method of claim 4, wherein the cancer is dependent on Bcl protein for growth and survival.   The method according to claim 6 or 7, wherein the Bcl protein is Bcl-2.   The method according to claim 6 or 7, wherein the Bcl protein is Bcl-xL.   5. The method of claim 4, wherein the cancer exhibits chromosomal translocation t (14; 18).   A method of treating a bcl-mediated disorder comprising administering a therapeutically effective amount of a compound according to claim 1 or 2 to a patient in need thereof.   12. The method of claim 11, wherein the bcl mediated disorder is cancer or neoplastic disease.   Cancer or neoplastic disease is acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia, myeloblastic leukemia, promyelocytic leukemia, myelomonocytic leukemia, monocytic leukemia, erythroleukemia, chronic leukemia, chronic Myeloid (granulocytic) leukemia, chronic lymphocytic leukemia, polycythemia vera, Hodgkin's disease, non-Hodgkin's disease; multiple myeloma, Waldenstrom macroglobulinemia, heavy chain disease, fibrosarcoma, myxosarcoma , Liposarcoma, chondrosarcoma, osteosarcoma, chordoma, hemangiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphatic endothelial sarcoma, synovial tumor, mesothelioma, Ewing tumor, leiomyosarcoma, rhabdomyosarcoma, colon Cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell cancer, basal cell cancer, adenocarcinoma, sweat gland cancer, sebaceous gland cancer, papillary cancer, papillary adenocarcinoma, cystic gland Cancer, medullary cancer, bronchial cancer, renal cell cancer, liver , Cholangiocarcinoma, choriocarcinoma, seminoma, fetal cancer, Wilms tumor, cervical cancer, uterine cancer, testicular cancer, lung cancer, small cell lung cancer, bladder cancer, epithelial cancer, glial Tumor, astrocytoma, medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblast 13. The method of claim 12, wherein the method is selected from the group consisting of a tumor and an endometrial cancer.   A method of treating a bcl-mediated disorder comprising co-administering a therapeutically effective amount of a chemotherapeutic agent and a therapeutically effective amount of the compound of claim 1 or 2 to a patient in need thereof.   15. The method of claim 14, wherein the bcl mediated disorder is cancer or neoplastic disease.   Cancer or neoplastic disease is acute leukemia, acute lymphocytic leukemia, acute myeloid leukemia, myeloblastic, promyelocytic, myelomonocytic, monocytic, erythroleukemia, chronic leukemia, chronic myeloid (granule Sphere) leukemia, chronic lymphocytic leukemia, polycythemia vera, Hodgkin's disease, non-Hodgkin's disease; multiple myeloma, Waldenstrom macroglobulinemia, heavy chain disease, fibrosarcoma, myxosarcoma, liposarcoma, Chondrosarcoma, osteosarcoma, chordoma, hemangiosarcoma, endothelial sarcoma, lymphangiosarcoma, lymphatic endothelial sarcoma, synovial tumor, mesothelioma, Ewing tumor, leiomyosarcoma, rhabdomyosarcoma, colon cancer, pancreas Cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell cancer, basal cell cancer, adenocarcinoma, sweat gland cancer, sebaceous gland cancer, papillary cancer, papillary adenocarcinoma, cystadenocarcinoma, marrow Cancer, bronchial cancer, renal cell cancer, liver cancer, bile duct cancer, choriocarcinoma, Epithelioma, embryonic cancer, Wilms tumor, cervical cancer, uterine cancer, testicular tumor, lung cancer, small cell lung cancer, bladder cancer, epithelial cancer, glioma, astrocytoma, medulloblastoma , Craniopharyngioma, ependymoma, pineal tumor, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, melanoma, neuroblastoma, retinoblastoma and endometrial cancer The method of claim 15, wherein the method is selected from:   15. The method of claim 14, wherein the bcl mediated disorder overexpresses Bcl protein.   15. The method of claim 14, wherein the bcl mediated disorder is dependent on Bcl protein for growth and survival.   The method according to claim 17 or 18, wherein the Bcl protein is Bcl-2.   The method according to claim 17 or 18, wherein the Bcl protein is Bcl-xL.   15. The method of claim 14, wherein the bcl-mediated disorder indicates chromosomal translocation t (14; 18).   15. A method according to claim 4, 11 or 14, wherein the compound is administered parenterally.   15. A method according to claim 4, 11 or 14, wherein the compound is administered intramuscularly, intravenously, subcutaneously, orally, topically or intranasally.   15. A method according to claim 4, 11 or 14, wherein the compound is administered systemically.   15. A method according to claim 4, 11 or 14, wherein the patient is a mammal.   15. A method according to claim 4, 11 or 14, wherein the patient is a primate.   15. A method according to claim 4, 11 or 14, wherein the patient is a human.